chr3-12604200-G-A

Position:

• chr3-12604200-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PM6_Strong PM1 PS3

This summary comes from the ClinGen Evidence Repository: The c.770C>T (p.Ser257Leu) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17603482,22389993, 23877478, 23312806, 25706034). In vitro functional studies provide some evidence that the p.Ser257Leu variant may impact protein function (PS3; PMID 17603482). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA235334/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:43 O:2
• Conservation: PhyloP100: 10.0

Genes affected

RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4	c.770C>T	p.Ser257Leu	missense_variant	7/17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.770C>T	p.Ser257Leu	missense_variant	7/17	1	NM_002880.4	ENSP00000251849	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:43 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:12

Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 05, 2020	The RAF1 c.770C>T; p.Ser257Leu variant (rs80338796) has been reported in multiple individuals diagnosed with Noonan syndrome (Razzaque 2007, Pandit 2007, Kobayashi 2010, Zarate 2014, Hopper 2015) or LEOPARD syndrome (Pandit 2007, Carcavilla 2013). The variant is reported as pathogenic in ClinVar by multiple sources (Variation ID: 13957) absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant is located in a region critical for the phosphorylation of serine-259 and its association with 14-3-3, which is involved in the negative regulation of RAF1 activity (Razzaque 2007, Kobayashi 2010). Functional characterization of the p.Ser257Leu variant protein indicates a loss of serine-259 phosphorylation and reduced association with 14-3-3 (Kobayashi 2010). This leads to an over-activation of MEK and ERK signaling (Razzaque 2007, Kobayashi 2010), consistent with the established disease mechanisms of Noonan Syndrome. Based on available information, this variant is considered to be pathogenic. References: Carcavilla A et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev Esp Cardiol (Engl Ed). 2013 May;66(5):350-6. Hopper R et al. Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation. Am J Med Genet A. 2015 Apr;167A(4):882-5. Kobayashi T et al. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010 Mar;31(3):284-94. Pandit B et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Razzaque M et al Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007 Aug;39(8):1013-7 Zarate Y et al. Unique cerebrovascular anomalies in Noonan syndrome with RAF1 mutation. J Child Neurol. 2014 Aug;29(8):NP13-7. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2022	Published functional studies demonstrate that S257L produces a gain of function effect with higher kinase activity than wild-type protein (Razzaque et al., 2007; Lee et al., 2011); Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26918529, 23877478, 30384889, 35050212, 32506814, 31219622, 34184824, 30417923, 25706034, 24033266, 23312806, 22389993, 17603483, 20052757, 24775816, 24803665, 28973083, 29084544, 28777121, 30732632, 30138938, 30055033, 30355600, 30105547, 21784453, 21440552, 28991257, 30050098, 29907801, 31395954, 31560489, 31324109, 31163979, 32573669, 32668055, 34136434, 33318624, 17603482, 32981126, 33673806, 32410215, 33240318, 32746448, 32368696, 34006472, 24957944, 9689060, 15520807, 29493581) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	RAF1: PS2:Very Strong, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 15, 2022	PP2, PM1, PM2, PS2_very_strong, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Noonan syndrome 5 Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 15, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	Mar 22, 2022	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.770C>T (p.Ser257Leu) in RAF1 gene has been reported in heterozygous state in many individuals affected with Noonan syndrome, both with and without multiple lentigines (Kobayashi T et al., 2010). Experimental studies have shown that this missense change leads to increased activation of MEK, ERK, and ELK in vitro (Razzaque et al., 2007). The p.Ser257Leu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ser at position 257 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser257Leu in RAF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted to be probably damaging by PolyPhen 2 and deleterious by SIFT. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	A heterozygous missense variant was identified, NM_002880.3(RAF1):c.770C>T in exon 7 of the RAF1 gene. This substitution is predicted to create a major amino acid change from a serine to a leucine at position 257 of the protein; NP_002871.1(RAF1):p.(Ser257Leu). The serine at this position has very high conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predictions of the pathogenicity of this variant are conflicting (FATHMM, PolyPhen2, MutationAssessor, PROVEAN). The variant is not present in the gnomAD population database. It is located within a mutational hotspot and has been previously reported as pathogenic in patients with Noonan syndrome (ClinGen RASopathy Variant Curation Expert Panel). Analysis of parental samples indicated that this variant is de novo. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17603482, 20052757). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.08). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013957). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 17603483, 23877478) and as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 17603482, 22389993, 23877478, 25706034). Different missense changes at the same codon (p.Ser257Pro, p.Ser257Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040600, VCV000618340). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Noonan syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics, Centre for Human Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Human Genetics	-	The RAF1 c.770C>T (p.Ser257Leu) variant has been reported in multiple individuals diagnosed with Noonan syndrome (Razzaque 2007, Pandit 2007, Kobayashi 2010, Zarate 2014, Hopper 2015) or LEOPARD syndrome (Pandit 2007, Carcavilla 2013). The variant is reported as pathogenic in ClinVar by multiple sources (Variation ID: 13957). -

Noonan syndrome Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.770C>T (p.Ser257Leu) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17603482,22389993, 23877478, 23312806, 25706034). In vitro functional studies provide some evidence that the p.Ser257Leu variant may impact protein function (PS3; PMID 17603482). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 05, 2015	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Nov 16, 2017	The RAF1 Ser257Leu variant has been previously reported in multiple Noonan syndrome cases (see literature), including at least 6 cases where the variant was found to arise de novo (Zarate YA, et al., 2013; Kobayashi T, et al., 2010; Pandit B, et al., 2007). We identified this variant in a young male patient diagnosed with Noonan syndrome. RAF1 Ser257Leu is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT and MutationTaster predict this variant to be deleterious, however PolyPhen-2 predicts this variant to be "benign". In summary, based on rarity in the general population, presence in multiple Noonan syndrome patients, the high rate of de novo occurrences and because the variant is located in a functional 'hotspot' we classify the RAF1 Ser257Leu as "pathogenic". -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2018	Variant summary: RAF1 c.770C>T (p.Ser257Leu) results in a non-conservative amino acid change located in the CR2 domain of the encoded protein sequence that is involved in regulatory phosphorylation and association with the 14-3-3 protein (Razzaque 2007, Pandit 2007). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246848 control chromosomes (gnomAD). c.770C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions, where several of these individuals also had hypertrophic cardiomyopathy or other cardiac manifestations (e.g. Razzaque 2007, Pandit 2007, Denayer 2010, Alfieri 2008, Croonen 2013, Zarare 2013, Lee 2011, Xu 2017). The variant has also been reported in some patients with LEOPARD syndrome (see e.g. Pandit 2007, Carcavilla 2013, Xu 2017). In all confirmed cases the variant occurred in heterozygous state as a de novo mutation (see e.g. Pandit 2007, Denayer 2010, Croonen 2013, Zarare 2013, Xu 2017). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, demonstrating increased kinase activity (Razzaque 2007), increased activation of MEK and ERK (Lee 2011) and altered signaling in cardiomyocytes consistent with that observed in cardiac hypertrophy (Dhandapany 2011). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (10x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 257 of the RAF1 protein (p.Ser257Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome, both with and without multiple lentigines (PMID: 17603482, 17603483, 20052757, 22389993, 23877478). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAF1 function (PMID: 17603482, 20052757). For these reasons, this variant has been classified as Pathogenic. -

LEOPARD syndrome 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 20, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PM5,PP2,PP3. -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 01, 2021

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 04, 2023

ACMG categories: PS3,PM1,PM2,PP3,PP5 -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 23, 2013

The p.Ser257Leu variant has been associated with the clinical features of RASopa thy disorders (Razzaque 2007, Pandit 2007). This variant has been reported to ha ve occurred de novo in sporadic cases. Individuals with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiomyopathy (80-95 %, Razzaque 2007, Pandit 2007). In summary, this variant meets criteria to be cl assified as pathogenic for RASopathy disorders in an autosomal dominant manner b ased upon published literature and de novo occurrence in affected individuals. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2021

The p.S257L pathogenic mutation (also known as c.770C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 770. The serine at codon 257 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in numerous individuals with a diagnosis of Noonan syndrome or LEOPARD syndrome, including as a de novo alteration in two individuals in which paternity was confirmed (Pandit B et al. Nat Genet, 2007 Aug;39:1007-12; Razzaque MA et al. Nat Genet, 2007 Aug;39:1013-7; Kobayashi T et al. Hum Mutat, 2010 Mar;31:284-94; Carcavilla A et al. Rev Esp Cardiol (Engl Ed), 2013 May;66:350-6; Xu S et al. BMC Med Genomics, 2017 10;10:62; Vasilescu C et al. J Am Coll Cardiol, 2018 11;72:2324-2338; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 26, 2021

- -

RAF1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Oct 21, 2020

This variant has been previously reported as a de novo change in patients with Noonan Syndrome (PMID: 17603482, 23877478) and LEOPARD syndrome 2 (PMID: 22389993, 24775816). This variant has been classified as Pathogenic by the ClinGen Rasopathy Expert Panel. Functional studies indicate that the p.Ser257Leu produces a gain-of-function effect with higher kinase activity than wild-type protein (PMID: 17603482). It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.770C>T (p.Ser257Leu) variant is classified as Pathogenic. -

Noonan syndrome with multiple lentigines Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.34	B;.;.
Vest4		0.85
MutPred		0.52		Gain of glycosylation at S252 (P = 0.0093);Gain of glycosylation at S252 (P = 0.0093);.;
MVP		0.96
MPC		0.57
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338796; hg19: chr3-12645699; COSMIC: COSV52574378; COSMIC: COSV52574378;