rs104894313

Positions:

• chr11-89284805-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM5 PP5_Very_Strong BP4

The NM_000372.5(TYR):​c.1217C>T​(p.Pro406Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,611,690 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P406A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (18 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 U:2 O:1
• Conservation: PhyloP100: 7.42

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000372.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-89284804-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1947187.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 11-89284805-C-T is Pathogenic according to our data. Variant chr11-89284805-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89284805-C-T is described in Lovd as [Pathogenic]. Variant chr11-89284805-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.037014306). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYR	NM_000372.5	c.1217C>T	p.Pro406Leu	missense_variant	4/5	ENST00000263321.6
TYR	XM_011542970.3	c.1217C>T	p.Pro406Leu	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYR	ENST00000263321.6	c.1217C>T	p.Pro406Leu	missense_variant	4/5	1	NM_000372.5	P1
TYR	ENST00000528243.1	n.215C>T		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 563 AN: 151820 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.00925

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00448

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00383 AC: 960 AN: 250392 Hom.: 4 AF XY: 0.00395 AC XY: 534 AN XY: 135346

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00855

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00463 AC: 6761 AN: 1459752 Hom.: 18 Cov.: 32 AF XY: 0.00453 AC XY: 3293 AN XY: 726248

Gnomad4 AFR exome AF: 0.000480

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00906

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00456

GnomAD4 genome AF: 0.00370 AC: 562 AN: 151938 Hom.: 5 Cov.: 32 AF XY: 0.00411 AC XY: 305 AN XY: 74288

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00269

Gnomad4 ASJ AF: 0.00925

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00416 Hom.: 1

Bravo AF: 0.00276

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00349 AC: 424

EpiCase AF: 0.00464

EpiControl AF: 0.00522

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The TYR (p.Pro406Leu) variant segregated in a family with type IB oculocutaneous albinism (PMID: 1903591). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000372.4:c.1217C>T in the TYR gene has an allele frequency of 0.011 in European (Finnish) subpopulation in the gnomAD database. The p.Pro406Leu (NM_000372.4 c.1217C>T) variant in TYR has been reported in at least 5 homozygous and 7 compound heterozygous individuals with clinical features of Oculocutaneous albinism type 1 (OCA type 1) (PMID: 18463683; 19320745; 19865097; 20861488; 25216246). In vitro function al studies provide evidence that the p.Pro406Leu variant may impact protein func tion (PMID: 1642278; 9242509; 11284711).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 27, 2019	The observed variant NM_000372.4 :c.1217C>T (p.Pro406Leu) is a missense variation found in exon 4 of the TYR gene. It is a known pathogenic variant and has been reported in the ExAC and gnomAD database with an allele frequency of 0.003489 and 0.003845, respectively. The in silico prediction of this variant is disease causing by MutationTaster2. The proband's parents are heterozygous carriers of the following mutations in the TYR gene: c.1147G>A (p.Asp383Asn) in exon 3 and c.1217C>T (p.pro406leu) in exon 4. As the parents are phenotypically normal, it is likely that these mutations are in a cis arrangement. The proband thus has both of the parent's mutations in trans with a third variant c.1110G>A, which is de novo. In summary, the variant meets the ACMG criteria to be classified as pathogenic based upon the evidence stated above. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PP2,PP3. This variant was detected in homozygous state. -

not provided Pathogenic:6 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TYR p.P406L variant was identified in 20 of 528 proband chromosomes (frequency: 0.038; 5 homozygotes, 6 compound heterozygotes, 4 heterozygotes) from individuals or families with Oculocutaneous Albinism (Giebel_1991_PMID:1903591; Hutton_2008_PMID:18463683; Khordadpoor-Deilamani_2016_PMID:26167114; Kalahroudi_2014_PMID:25216246; Norman_2017_PMID:28667292; Gao_2017_PMID:28451379). This variant was also identified as a heterozygous variant in patient with basal cell carcinoma from a cohort of 287 patients with a suspected predisposition of skin cancer (Hu_2011_PMID:21906913), and as a homozygous variant in one of 138 patients with primary cutaneous melanoma (Council_2009_PMID:19320745). The variant was identified in dbSNP (ID: rs104894313) and ClinVar (classified as pathogenic by Ambry Genetics, EGl Genetics and three other laboratories, and as likely pathogenic by Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and two other laboratories). The variant was identified in control databases in 1104 of 281766 chromosomes (7 homozygous) at a frequency of 0.003918 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 273 of 25062 chromosomes (freq: 0.01089), Ashkenazi Jewish in 87 of 10350 chromosomes (freq: 0.008406), Other in 35 of 7178 chromosomes (freq: 0.004876), European (non-Finnish) in 555 of 128466 chromosomes (freq: 0.00432), Latino in 69 of 35262 chromosomes (freq: 0.001957), South Asian in 57 of 30608 chromosomes (freq: 0.001862), African in 26 of 24912 chromosomes (freq: 0.001044), and East Asian in 2 of 19928 chromosomes (freq: 0.0001). The p.Pro406 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies demonstrated that the p.P406L variant destabilizes tyrosinase structure and results in reduced protein activity compared to wildtype (Giebel_1991_PMID_1903591; Dolinksa_2017_PMID_27775880; Toyofuku_2001_PMID_11284711; Spritz_1997_PMID_9242509). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	Reported in additional patients with features of oculocutaneous albinism in the literature, however, some of these patients also had additional TYR variants on the same allele (in cis), including p.(A355P) and p.(P431T), or with the phase of the variants not confirmed (PMID: 1903591, 13680365, 15146472, 18463683, 21541274, 34897530); Published functional studies suggest a damaging effect with temperature-sensitive tyrosine hydroxylase activity and abnormal subcellular trafficking compared to wild type (PMID: 1429711, 9242509, 11284711, 27775880); 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: 24123366, 21906913, 25333069, 28667292, 22734612, 27887888, 31382929, 31322791, 31980526, 34426522, 31589614, 31719542, 38465142, 37685839, 33995009, 33808351, 32411182, 38542347, 1429711, 34360537, 9242509, 1903591, 13680365, 15146472, 20861488, 25216246, 11284711, 27775880, 34897530, 37734845, 18463683, 21541274, 28976636, 30609409, 34838614, 37217489, 35741834) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 406 of the TYR protein (p.Pro406Leu). This variant is present in population databases (rs104894313, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1903591, 22734612, 25216246, 27734839). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3777). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYR protein function. Experimental studies have shown that this missense change affects TYR function (PMID: 1429711, 9242509, 11284711). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TYR: PM3:Very Strong, PM1, PM2, PM5, PS3:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2022	- -

Oculocutaneous albinism type 1B Pathogenic:4 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Apr 11, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. These variants have been previously reported as disease-causing [PMID 1642278, 28266639, 1903591, 27775880, 25333069, 21906913, 28667292, 24123366, 9242509, 11284711, 1429711] -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with oculocutaneous albinism type IA (MIM#203100) and type IB (MIM#606952). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (1190 heterozygotes, 7 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or very highly conserved with a moderate amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a hypomorphic allele and has been reported in multiple individuals with oculocutaneous albinism (PMID: 28667292, 31719542). It has also be reported as pathogenic and VUS in ClinVar. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This OCA1B-related variant is biochemically similar to the wild type but with reduced enzyme activity to 35% (PMID: 27775880). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.1237delG; p.Glu413Lysfs*72) in a recessive disease. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Pathogenic, criteria provided, single submitter	research	Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe	-	- -

Oculocutaneous albinism Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	The p.Pro406Leu (NM_000372.4 c.1217C>T) variant in TYR has been reported in at l east 5 homozygous and 7 compound heterozygous individuals with clinical features of Oculocutaneous albinism type 1 (OCA type 1), and segregated with disease in 3 affected relatives from 1 family (Giebel 1991, Hutton 2008, Council 2009, Wei 2010, Hu 2011, Gargiulo 2011, Kalahroudi 2014, Rooryck 2008, Gronskov 2009, and Jaworek 2011). This variant has been identified in 1% (275/25738) of Finnish chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitut e.org; dbSNP rs104894313, rs62645921). This variant has also been reported in Cl inVar (Variation ID#3777) as pathogenic or likely pathogenic. In vitro function al studies provide evidence that the p.Pro406Leu variant may impact protein func tion (Tripathi 1992, Spritz 1997, and Toyofuku 2001). It should be noted that so me studies have indicated that the pseudogene harbors this same variant. In summ ary, although additional studies are required to fully establish its significanc e, this variant is likely pathogenic for OCA type 1 in an autosomal recessive ma nner based upon case observations, segregation studies and in vitro data. ACMG/A MP Criteria applied: PM3 (upgraded to strong based on multiple occurences), PP1, PP3, PP5 (Richards 2015). Although the variant has been confirmed to occur in t he functional copy of the gene in this individual, we cannot guarantee that the evidence in the literature was based on observations in the functional gene. Ple ase note that, due to the technical limitations of the next generation sequencin g and Sanger confirmation assays, the TYR pseudogene cannot be reliably avoided. Therefore, before making clinical decisions regarding this variant, further tes ting via targeted assays that guarantee avoidance of TYR pseudogene would be req uired to confirm the presence of this variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	Variant summary: TYR c.1217C>T (p.Pro406Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0038 in 250392 control chromosomes in the gnomAD database, including 4 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.0038 vs 0.0056), allowing no conclusion about variant significance. c.1217C>T has been reported in the literature in individuals affected with Oculocutaneous Albinism. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in less catalytic activity than the wild-type. Twenty-one clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/likely pathogenic n=18, benign n=1, VUS n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 24, 2017	The TYR c.1217C>T (p.Pro406Leu) missense variant has been reported in five studies in which it is found in at least 25 patients with oculocutaneous albinism (OCA) including in 13 patients in a homozygous state, four patients in a compound heterozygous state, two patients in a heterozygous state, and six individuals whose zygosity was not reported (Giebel et al. 1991; Hutton et al. 2008; Gargiulo et al. 2011; Jaworek et al. 2012; Ghodsinejad Kalahroudi et al. 2014). When clinical subtypes were described, the majority of affected individuals were reported to have OCA type 1. The variant was also detected in nine unaffected heterozygous carriers (Giebel LB et al. 1991). Khordadpoor-Deilamani et al. (2016) additionally found one patient with the p.Pro406Leu variant in a heterozygous state who also carried a homozugous frameshift variant in the SLC45A2 gene. The p.Pro406Leu variant was absent from at least 372 control chromosomes but is reported at a frequency of 0.00696 in the European population of the 1000 Genomes Project. Giebel et al. (1991) demonstrated that the tyrosinase activity in HeLa cells transfected with the p.Pro406Leu variant had only 7% of the activity of wild type. Toyofuku et al. (2001) expressed the p.Pro406Leu variant in COS7 cells and demonstrated that the variant protein is mislocalized, is more sensitive to endoglycosidase H digestion, and degrades more rapidly than wild type protein. Based on the collective evidence, the p.Pro406Leu variant is classified as pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2014

- -

Abnormality of the skin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Tyrosinase-negative oculocutaneous albinism;CN028925:Ocular albinism with congenital sensorineural hearing loss Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

TYR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2024

The TYR c.1217C>T variant is predicted to result in the amino acid substitution p.Pro406Leu. This variant has been reported in both the homozygous and compound heterozygous states in multiple individuals with oculocutaneous albinism (Giebel et al. 1991. PubMed ID: 1903591; King et al. 2003. PubMed ID: 13680365; Hutton & Spritz. 2008. PubMed ID: 18463683). Functional studies using protein expression in cell culture have shown that the p.Pro406Leu variant results in reduced tyrosinase activity compared to wild-type (Giebel et al. 1991. PubMed ID: 1903591; Dolinska et al. 2017. PubMed ID: 27775880). This variant is reported in 1.1% of alleles in individuals of European (Finnish) descent in gnomAD and with a global allele frequency of 0.39%, including multiple homozygous individuals, indicating this variant is relatively common and may have reduced penetrance in the homozygous state. Given all the evidence, we interpret this variant as pathogenic. -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Hearing impairment Uncertain:1

Uncertain significance, flagged submission

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM5_Strong, PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.037	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.88
MVP		1.0
MPC		0.059
ClinPred		0.020	T
GERP RS		4.7
Varity_R		0.48
gMVP		0.88

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: rs104894313; hg19: chr11-89017973; COSMIC: COSV99074517;