rs201580493

chr6-64307042-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001142800.2(EYS):c.6119T>A(p.Val2040Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00117 in 1,542,280 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (12 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:6
• Conservation: PhyloP100: 5.49

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009310007).
• BP6: Variant 6-64307042-A-T is Benign according to our data. Variant chr6-64307042-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137257.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=2}. Variant chr6-64307042-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00112 (1556/1390320) while in subpopulation MID AF= 0.0277 (156/5624). AF 95% confidence interval is 0.0242. There are 12 homozygotes in gnomad4_exome. There are 793 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.6119T>A	p.Val2040Asp	missense_variant	30/43	ENST00000503581.6
EYS	NM_001292009.2	c.6119T>A	p.Val2040Asp	missense_variant	30/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.6119T>A	p.Val2040Asp	missense_variant	30/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.6119T>A	p.Val2040Asp	missense_variant	30/44	1		P2

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 151842 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00683

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00817

GnomAD3 exomes AF: 0.00171 AC: 262 AN: 152886 Hom.: 1 AF XY: 0.00167 AC XY: 136 AN XY: 81226

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.00377

Gnomad ASJ exome AF: 0.00542

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00536

GnomAD4 exome AF: 0.00112 AC: 1556 AN: 1390320 Hom.: 12 Cov.: 27 AF XY: 0.00116 AC XY: 793 AN XY: 686318

Gnomad4 AFR exome AF: 0.000797

Gnomad4 AMR exome AF: 0.00346

Gnomad4 ASJ exome AF: 0.00510

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.0000205

Gnomad4 NFE exome AF: 0.000810

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00168 AC: 256 AN: 151960 Hom.: 1 Cov.: 32 AF XY: 0.00194 AC XY: 144 AN XY: 74276

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00682

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00808

Alfa AF: 0.00192 Hom.: 0

Bravo AF: 0.00232

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00180 AC: 38

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: EYS c.6119T>A (p.Val2040Asp) results in a non-conservative amino acid change located in the first laminin G repeat domain (IPR001791) 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 0.0017 in 152886 control chromosomes, predominantly at a frequency of 0.0038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.11 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism. c.6119T>A has been reported in the literature in individuals affected with Retinitis Pigmentosa (Audo_2010, Barragan_2010, Sharon_2020, Dinero_2020). These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, two as likely benign, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 17, 2014	- -

Retinitis pigmentosa Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinitis pigmentosa 25 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	EYS: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.91	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.42
MVP		0.66
MPC		0.058
ClinPred		0.036	T
GERP RS		5.1
Varity_R		0.38
gMVP		0.17

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: rs201580493; hg19: chr6-65016935; COSMIC: COSV65520896;