rs17403955

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

EYS-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
retinitis pigmentosa 25
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

EYS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 93610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.4081A>G	p.Ile1361Val	missense_variant	Exon 26 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.4081A>G	p.Ile1361Val	missense_variant	Exon 26 of 44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 link	c.4081A>G	p.Ile1361Val	missense_variant	Exon 26 of 43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 link	c.4081A>G	p.Ile1361Val	missense_variant	Exon 26 of 44	1		ENSP00000359655.3		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

GnomAD2 exomes

AF:

0.119

AC:

18240

AN:

153680

AF XY:

0.119

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 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

African (AFR)

AF:

0.0303

AC:

958

AN:

31578

American (AMR)

AF:

0.135

AC:

4819

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.0797

AC:

2004

AN:

25160

East Asian (EAS)

AF:

0.145

AC:

5170

AN:

35732

South Asian (SAS)

AF:

0.105

AC:

8279

AN:

79200

European-Finnish (FIN)

AF:

0.0808

AC:

3981

AN:

49270

Middle Eastern (MID)

AF:

0.0573

AC:

326

AN:

5692

European-Non Finnish (NFE)

AF:

0.141

AC:

152344

AN:

1078460

Other (OTH)

AF:

0.124

AC:

7202

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

8846

17692

26537

35383

44229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5580

11160

16740

22320

27900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.101

AC:

15349

AN:

152126

Hom.:

927

Cov.:

AF XY:

0.0993

AC XY:

7392

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0364

AC:

1513

AN:

41532

American (AMR)

AF:

0.124

AC:

1896

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.0720

AC:

250

AN:

3470

East Asian (EAS)

AF:

0.166

AC:

856

AN:

5156

South Asian (SAS)

AF:

0.112

AC:

542

AN:

4824

European-Finnish (FIN)

AF:

0.0739

AC:

784

AN:

10608

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9186

AN:

67962

Other (OTH)

AF:

0.0975

AC:

206

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

723

1447

2170

2894

3617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.122

Hom.:

2574

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

Sep 19, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 11, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa 25

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.042

.;T

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

PhyloP100

0.16

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

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over