6-64591465-C-G

Position:

chr6-64591465-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001142800.2(EYS):c.4402G>C(p.Asp1468His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,551,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 0.134

Variant links:

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]

EYS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01108256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.4402G>C	p.Asp1468His	missense_variant	26/43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 linkuse as main transcript	c.4402G>C	p.Asp1468His	missense_variant	26/44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.4402G>C	p.Asp1468His	missense_variant	26/43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.4402G>C	p.Asp1468His	missense_variant	26/44	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000977

AC:

AN:

153600

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

81470

show subpopulations

Gnomad AFR exome

AF:

0.00164

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000422

AC:

AN:

1399168

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

690104

show subpopulations

Gnomad4 AFR exome

AF:

0.00101

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000379

GnomAD4 genome

AF:

0.000441

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00155

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.000510

ExAC

AF:

0.000278

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2019	Reported in the homozygous state in patients with retinitis pigmentosa in published literature, however, these individuals were also homozygous for the c.3443+1G>T pathogenic variant in the EYS gene (Ge et al., 2015; Sengillo et al, 2018); Observed with additional EYS variants, including the c.3443+1G>T pathogenic variant, in an individual with peripheral dystrophy, however, segregation data was not provided to determine whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Wang et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25097241, 29550188, 26667666) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2018	The EYS c.4402G>C; p.Asp1468His variant (rs778752557) is reported in the medical literature in two individuals with retinitis pigmentosa, one of whom carried an alternative molecular explanation for disease (Ge 2015, Wang 2014). The variant is described in the ClinVar database (Variation ID: 195938) and is listed in the Genome Aggregation Database with an allele frequency of 0.2% (30/16324 alleles) in the African population. The aspartic acid at codon 1468 is moderately conserved and computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly damaging) predict conflicting effects of this variant on protein structure/function. Although there is information indicating this variant may be likely benign, there is insufficient evidence to classify the variant with certainty. Pathogenic EYS variants are causative for autosomal recessive retinitis pigmentosa (MIM: 602772). References: Ge Z et al. NGS-based Molecular diagnosis of 105 eyeGENE probands with Retinitis Pigmentosa. Sci Rep. 2015 Dec 15;5:18287. Wang J et al. Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2014 Aug 5;55(10):6213-23. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1468 of the EYS protein (p.Asp1468His). This variant is present in population databases (rs778752557, gnomAD 0.2%). This missense change has been observed in individual(s) with retinal disease. However, this variant has frequently been identified on the same chromosome as other EYS variants, making its clinical significance uncertain (PMID: 25097241, 26667666, 29550188). ClinVar contains an entry for this variant (Variation ID: 195938). 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 EYS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinitis pigmentosa 25

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Autosomal recessive retinitis pigmentosa

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 31, 2020

- -

EYS-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2024

The EYS c.4402G>C variant is predicted to result in the amino acid substitution p.Asp1468His. This variant has been reported in individuals with retinitis pigmentosa; however, in several of these cases it was determined to be on the same allele (in cis) with the pathogenic variant c.3443+1G>T as well as the uncertain missense variant c.3250A>C (p.Thr1084Pro) (Wang et al. 2014. PubMed ID: 25097241; Ge et al. 2015. PubMed ID: 26667666; Sengillo et al. 2018. PubMed ID: 29550188). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign by itself, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 08, 2019

- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Asp1468His variant in EYS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PM3-P. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

.;T

Eigen

Benign

-0.012

Eigen_PC

Benign

-0.0031

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.020

D;D

Sift4G

Benign

0.20

T;T

Polyphen

1.0

D;D

Vest4

0.13

MVP

0.45

MPC

0.026

ClinPred

0.081

GERP RS

4.0

Varity_R

0.085

gMVP

0.095

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over