rs1800386

Positions:

• chr12-6018667-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PP2 PP5 BP4 BS2_Supporting

The NM_000552.5(VWF):​c.4751A>G​(p.Tyr1584Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00344 in 1,613,678 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (15 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:18 U:7 O:4
• Conservation: PhyloP100: 3.59

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a helix (size 9) in uniprot entity VWF_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000552.5
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
• PP5: Variant 12-6018667-T-C is Pathogenic according to our data. Variant chr12-6018667-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity, risk_factor]. Clinvar id is 310.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, risk_factor=1, not_provided=2, Uncertain_significance=7, Pathogenic=4}. Variant chr12-6018667-T-C is described in Lovd as [Pathogenic]. Variant chr12-6018667-T-C is described in Lovd as [Likely_pathogenic]. Variant chr12-6018667-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.044336706). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 343 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.4751A>G	p.Tyr1584Cys	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.4751A>G	p.Tyr1584Cys	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.4751A>G	p.Tyr1584Cys	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-24733A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 343 AN: 151988 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00266 AC: 667 AN: 251146 Hom.: 4 AF XY: 0.00269 AC XY: 365 AN XY: 135768

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00338

Gnomad NFE exome AF: 0.00412

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00357 AC: 5212 AN: 1461572 Hom.: 15 Cov.: 41 AF XY: 0.00349 AC XY: 2534 AN XY: 727026

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00437

Gnomad4 NFE exome AF: 0.00412

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00226 AC: 343 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.00207 AC XY: 154 AN XY: 74346

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00280 Hom.: 0

Bravo AF: 0.00197

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00293 AC: 356

EpiCase AF: 0.00447

EpiControl AF: 0.00456

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:18 Uncertain:7 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:8 Uncertain:4 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2023	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	The VWF c.4751A>G; p.Tyr1584Cys variant (rs1800386) has been described in numerous individuals and families affected with von Willebrand disease type I (Bowen 2004, James 2007, O’Brien 2003). While this variant segregates with disease in multiple families, it also exhibits incomplete penetrance in some families (Bowen 2005, O’Brien 2003). This variant is reported in ClinVar (Variation ID: 310). It is found in the general population at an overall allele frequency of 0.26% (743/282486 alleles, 4 homozygotes) in the Genome Aggregation Database. The tyrosine at codon 1584 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.639). Functional studies indicate that this variant protein results in decreased protein synthesis and increased cellular retention in vitro, with increased susceptibility of VWF proteolysis in vivo (Bowen 2005, O’Brien 2003, Pruss 2011). Correlative studies further suggest that in individuals carrying this variant, VWF:Ag levels are lowest in those with blood group O (Davies 2007). Based on available information, the p.Tyr1584Cys variant is considered to be likely pathogenic. REFERENCES Bowen D et al. An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Blood. 2004 Feb 1;103(3):941-7. PMID: 14525793. Bowen D et al. The prevalence of the cysteine1584 variant of von Willebrand factor is increased in type 1 von Willebrand disease: co-segregation with increased susceptibility to ADAMTS13 proteolysis but not clinical phenotype. Br J Haematol. 2005 Mar;128(6):830-6. PMID: 15755288. Davies JA et al. Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group. Blood. 2007;109(7):2840-2846. PMID: 17119126. James P et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007 Jan 1;109(1):145-54. PMID: 17190853. O'Brien L et al. Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease. Blood. 2003 Jul 15;102(2):549-57. PMID: 12649144. Pruss C et al. Pathologic mechanisms of type 1 VWD mutations R1205H and Y1584C through in vitro and in vivo mouse models. Blood. 2011 Apr 21;117(16):4358-66. PMID: 21346256. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2024	Reported as the most common variant seen in individuals with type 1 von Willebrand disease, with possible codominant inheritance, but is noted to have incomplete penetrance (PMID: 17190853, 12649144, 20301765); Described as a susceptibility variant, increasing the risk to develop von Willebrand disease type 1, but not sufficient to make a diagnosis of von Willebrand disease in the absence of clinical features (PMID: 15755288); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15842375, 22197721, 22995991, 19506354, 27920237, 28091443, 27380589, 34708896, 31064749, 37845247, 23355534, 21346256, 14525793, 23426949, 12649144, 17610557, 16985174, 16634747, 27596108, 26988807, 17080221, 30817071, 30722078, 34426522, 33556167, 37466676, 36703223, 35552711, 36696193, 33113216, 35753512, 33477601, 35505650, 34828413, 15755288, 17190853, 38040335, 36754679) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 30, 2022	BS4, PP5_moderate, PS3, PS4_moderate -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The VWF p.Tyr1584Cys variant is commonly reported in associated with type 1 von Willebrand disease (VWD) and was originally identified in 21/150 patients with type 1 VWD from 70 families, however not all family members with the variant was affected with VWD suggesting incomplete penetrance (O'Brien_2003_PMID:12649144). The variant was also identified in 19/76 patients with VWD from 30 families, however the variant did not co-segregate with disease in four families, suggesting incomplete penetrance and that the variant may increase risk but not necessarily be causal for disease (Bowen_2005_PMID:15755288). The variant was identified in dbSNP (ID: rs1800386), LOVD 3.0 and in ClinVar (classified as likely pathogenic by Quest Diagnostics Nichols Institute San Juan Capistrano, pathogenic by Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital and as a VUS by GeneDx and Ambry Genetics). The variant was not identified in Cosmic. The variant was found in control databases in 743 of 282486 chromosomes (4 homozygous) at a frequency of 0.00263 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 519 of 128972 chromosomes (freq: 0.004024), European (Finnish) in 86 of 25048 chromosomes (freq: 0.003433), Other in 22 of 7212 chromosomes (freq: 0.00305), Ashkenazi Jewish in 29 of 10358 chromosomes (freq: 0.0028), Latino in 60 of 35414 chromosomes (freq: 0.001694), African in 14 of 24934 chromosomes (freq: 0.000562) and South Asian in 13 of 30610 chromosomes (freq: 0.000425); it was not observed in the East Asian population. A case study of a man diagnosed with mild haemophilia A and type 1 VWD identified the VWF Y1584C variant as well as a variant in the FVIII gene (A723T); his daughter also had both mutations and had a slightly higher bleeding score than normal while his father carried just the VWF Y1584C variant and had a normal bleeding score (Daidonee_2017_27380589). This variant was identified in another patient with mild hemophilia A who also had a variant in the FVIII gene (R2150C) (Boylan_2015_25780857). A study of a Nigerian population with a history of bleeding suggested that the Y1584C variant was significantly associated with bleeding compared to controls (Ezigbo_2017_28091443). Functional studies of the Y1584C variant have demonstrated conflicting results. One functional study of the Y1584C variant suggested normal function compared to wild-type as well as another functional study using patient derived blood outgrowth endothelial cells did not show any impaired function in the Y1584C mutant compared to healthy control cells (Growneveld_2014_PMID:25103891; Wang_2013_PMID:23426949). However another functional study of the Y1584C variant from patient blood outgrowth endothelial cells demonstrated impaired function including reduced VWF mRNA and protein expression compared to wild-type (Starke_2013_PMID:23355534). Further, mouse and cell models of the Y1584C variant suggested impaired function compared to wild-type (Pruss_2011_PMID:21346256). The variant occurs outside of the splicing consensus sequence however 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer) predict the loss of a 5' splice site. However this is not a known splice site and is only predicted by 2 of 4 programs (MaxEntScan, GeneSplicer) to be a 5' splice site with the wildtype allele. No in silico splicing programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a change in splicing at the consensus sequence. The p.Tyr1584 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be -
Likely pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	VWF: PS3:Moderate, PS4:Moderate, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 28, 2021	In the published literature, this variant has been reported in more frequently in individuals with Type I von Willebrand disease (vWD) than unaffected individuals (PMID: 12649144 (2003), 17119126 (2007)), 28091443 (2017)). Functional studies have shown that this variant causes decreased VWF protein levels, decreased VWF protein function, (PMID: 16985174 (2007), 23355534 (2013), 23426949 (2013), 25103891 (2014)), and increased susceptibility of the VWF protein to proteolysis (PMID: 14525793 (2004), 19506354 (2009), 21346256 (2011)). This variant has also been described as having reduced penetrance and a mild or moderate phenotypic effect (PMID: 16985174 (2007)).Based on the available information, this variant is classified as pathogenic. -

von Willebrand disease type 1 Pathogenic:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	May 31, 2022	- -
risk factor, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jan 26, 2022	- -

von Willebrand disease type 2 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 06, 2021	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	May 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 28, 2020	This VWF variant is a known risk factor allele and has been reported in numerous individuals with von Willebrand disease. Functional assays have shown that this variant results in a decrease of protein production and expression when compared to wildtype. VWF c.4751A>G is located within the A2 collagen functinal domain. This variant (rs1800386) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%): gnomAD: 743/282486 alleles; 0.26%, 4 homozygotes). VWF c.4751A>G has been reported in ClinVar. We consider this variant to be likely pathogenic. -

Hereditary von Willebrand disease Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2022	The p.Tyr1584Cys variant in VWF has been reported in >15 individuals with Von Willebrand Disease (VWD) and segregated with disease in at least 3 affected individuals from 3 families. However, this variant has also been associated with a milder phenotype and may display reduced penetrance, as not all individuals who harbor the variant are clinically affected (O'Brien 2003 PMID: 12649144, Bellissimo 2012 PMID: 22197721, Daidone 2017 PMID:27380589, Vangenechten 2019 PMID: 30722078, Freitas 2019 PMID: 30817071). It has also been identified in 0.402% (519/128972) of European chromosomes, including 4 homozygous observations, by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar (Variation ID: 310). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (O'Brien 2003 PMID: 12649144, Pruss 2011 PMID: 21346256); however, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes decreased thrombus formation (Pruss 2011 PMID: 21346256). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic with reduced penetrance for autosomal dominant VWD. ACMG/AMP Criteria applied: PS3, PS4_Moderate, PP1. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Dec 05, 2013	- -

von Willebrand disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2024

Variant summary: VWF c.4751A>G (p.Tyr1584Cys) results in a non-conservative amino acid change located in the 2nd type A domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 1606724 control chromosomes, predominantly at a frequency of 0.0041 within the Non-Finnish European subpopulation in the gnomAD database (v4.1 dataset), including 14 homozygotes. The observed relatively high frequency together with the homozygous occurrences might indicate a benign nature for the variant. On the other hand, c.4751A>G has been reported as the most common variant found in individuals affected with type 1 Von Willebrand Disease, and it has been found in many individuals and families affected with the disease (e.g. O'Brien_2003, Bowen_2005, James_2007, Borras_2017, Freitas_2019, Vangenechten_2019), although in many families a reduced penetrance and a milder disease phenotype was described (e.g. O'Brien_2003, Bowen_2005, Bellissimo_2012). Experimental studies have demonstrated that the Y1584C variant results in decreased biosynthesis and secretion in vitro (e.g. O'Brien_2003), together with an increased susceptibility to proteolysis by ADAMTS13 (e.g. Pruss_2011). Additionally, in a mouse model the variant protein had decreased plasma levels and resulted in reduced thrombus formation (Pruss_2011). In recent large GWAS analyses, the variant was found to be present at higher frequencies in European populations (0.3%-0.44%), and was found to be associated with the risk of von Willebrand disease (log(odds ratio (OR)) = 2.09, P = 8.7E-09), and with a decrease in von Willebrand factor and FVIII levels (e.g. Sun_2022, Pankratz_2022). The following publications have been ascertained in the context of this evaluation (PMID: 22197721, 28971901, 15755288, 30817071, 17190853, 12649144, 21346256, 30722078, 35197637, 35552711). ClinVar contains an entry for this variant (Variation ID: 310). Based on the evidence outlined above, the variant seems to be associated with the disease with an incomplete penetrance, and therefore was classified as likely pathogenic. -

Thrombus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

VWF-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

The VWF c.4751A>G variant is predicted to result in the amino acid substitution p.Tyr1584Cys. This variant has been reported to segregate with disease phenotype in several families with von Willebrand Disease (VWD) Type I and was also found in apparent controls who were later found to have some symptoms of VWD (O’Brien et al. 2003. PubMed ID: 12649144; Bellissimo et al. 2012. PubMed ID: 22197721; Bowen and Collins. 2004. PubMed ID: 14525793). The p.Tyr1584Cys substitution has been reported to make VWF protein more susceptible to ADAMTS13 – mediated proteolysis (Bowen and Collins. 2004. PubMed ID: 14525793; Pruss et al. 2013. PubMed ID: 21346256) and has been associated with decreased levels of VWF protein, especially in patients with blood group O (Davies et al. 2009. PubMed ID: 19506354). The c.4751A>G variant displays variable penetrance among patients from the studies mentioned above, and taken together, available data indicate that this variant is likely to cause or at least increase risk of disease. We categorize this variant as likely pathogenic; however, in the absence of clinical features, it may not be sufficient to make a clinical diagnosis of VWD. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2014

- -

Thrombocytopenia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

von Willebrand disease, type 1, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.044	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.82
MVP		0.81
MPC		0.39
ClinPred		0.085	T
GERP RS		5.0
Varity_R		0.79
gMVP		0.89

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: rs1800386; hg19: chr12-6127833;