rs17403955

Positions:

chr6-64591786-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001142800.2(EYS):c.4081A>G(p.Ile1361Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,550,880 control chromosomes in the GnomAD database, including 13,838 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1361M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 927 hom., cov: 33)

Exomes 𝑓: 0.13 ( 12911 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.164

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018867254).

BP6

Variant 6-64591786-T-C is Benign according to our data. Variant chr6-64591786-T-C is described in ClinVar as [Benign]. Clinvar id is 93610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64591786-T-C is described in Lovd as [Likely_benign]. Variant chr6-64591786-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.4081A>G	p.Ile1361Val	missense_variant	26/43	ENST00000503581.6
EYS	NM_001292009.2 linkuse as main transcript	c.4081A>G	p.Ile1361Val	missense_variant	26/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.4081A>G	p.Ile1361Val	missense_variant	26/43	5	NM_001142800.2	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.4081A>G	p.Ile1361Val	missense_variant	26/44	1		P2	Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15354

AN:

152008

Hom.:

930

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0365

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.0720

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0739

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.0986

GnomAD3 exomes

AF:

0.119

AC:

18240

AN:

153680

Hom.:

1234

AF XY:

0.119

AC XY:

9728

AN XY:

81536

show subpopulations

Gnomad AFR exome

AF:

0.0306

Gnomad AMR exome

AF:

0.136

Gnomad ASJ exome

AF:

0.0820

Gnomad EAS exome

AF:

0.175

Gnomad SAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.0820

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.132

AC:

185083

AN:

1398754

Hom.:

12911

Cov.:

AF XY:

0.132

AC XY:

91038

AN XY:

689902

show subpopulations

Gnomad4 AFR exome

AF:

0.0303

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.0797

Gnomad4 EAS exome

AF:

0.145

Gnomad4 SAS exome

AF:

0.105

Gnomad4 FIN exome

AF:

0.0808

Gnomad4 NFE exome

AF:

0.141

Gnomad4 OTH exome

AF:

0.124

GnomAD4 genome

AF:

0.101

AC:

15349

AN:

152126

Hom.:

927

Cov.:

AF XY:

0.0993

AC XY:

7392

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0364

Gnomad4 AMR

AF:

0.124

Gnomad4 ASJ

AF:

0.0720

Gnomad4 EAS

AF:

0.166

Gnomad4 SAS

AF:

0.112

Gnomad4 FIN

AF:

0.0739

Gnomad4 NFE

AF:

0.135

Gnomad4 OTH

AF:

0.0975

Alfa

AF:

0.127

Hom.:

1965

Bravo

AF:

0.105

TwinsUK

AF:

0.135

AC:

501

ALSPAC

AF:

0.128

AC:

494

ESP6500AA

AF:

0.0354

AC:

ESP6500EA

AF:

0.140

AC:

446

ExAC

AF:

0.0954

AC:

2106

Asia WGS

AF:

0.122

AC:

422

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 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. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Retinitis pigmentosa

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis pigmentosa 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.2

DANN

Benign

0.76

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.078

Sift

Benign

0.54

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.0010

B;B

Vest4

0.021

MPC

0.010

ClinPred

0.00052

GERP RS

-1.2

Varity_R

0.031

gMVP

0.022

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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