NM_001142800.2:c.3973C>G

Variant names:

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.3973C>G(p.Gln1325Glu) 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 1,547,756 control chromosomes in the GnomAD database, including 13,776 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1325K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 924 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12852 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.11

Publications

14 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=0.0019658804).

BP6

Variant 6-64591894-G-C is Benign according to our data. Variant chr6-64591894-G-C is described in ClinVar as Benign. ClinVar VariationId is 93608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.3973C>G	p.Gln1325Glu	missense_variant	Exon 26 of 43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2 link	c.3973C>G	p.Gln1325Glu	missense_variant	Exon 26 of 44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 link	c.3973C>G	p.Gln1325Glu	missense_variant	Exon 26 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7 link	c.3973C>G	p.Gln1325Glu	missense_variant	Exon 26 of 44	1		ENSP00000359655.3

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15349

AN:

152054

Hom.:

926

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0364

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.0723

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0740

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.0989

GnomAD2 exomes

AF:

0.117

AC:

17920

AN:

152598

AF XY:

0.118

show subpopulations

Gnomad AFR exome

AF:

0.0301

Gnomad AMR exome

AF:

0.134

Gnomad ASJ exome

AF:

0.0803

Gnomad EAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.0815

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.132

AC:

183552

AN:

1395584

Hom.:

12852

Cov.:

AF XY:

0.131

AC XY:

90292

AN XY:

688332

show subpopulations

African (AFR)

AF:

0.0299

AC:

943

AN:

31536

American (AMR)

AF:

0.134

AC:

4758

AN:

35554

Ashkenazi Jewish (ASJ)

AF:

0.0789

AC:

1980

AN:

25088

East Asian (EAS)

AF:

0.144

AC:

5154

AN:

35696

South Asian (SAS)

AF:

0.104

AC:

8184

AN:

78982

European-Finnish (FIN)

AF:

0.0806

AC:

3971

AN:

49240

Middle Eastern (MID)

AF:

0.0574

AC:

327

AN:

5692

European-Non Finnish (NFE)

AF:

0.140

AC:

151077

AN:

1075924

Other (OTH)

AF:

0.124

AC:

7158

AN:

57872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

8194

16388

24581

32775

40969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5522

11044

16566

22088

27610

<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:

15345

AN:

152172

Hom.:

924

Cov.:

AF XY:

0.0992

AC XY:

7380

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0363

AC:

1508

AN:

41530

American (AMR)

AF:

0.124

AC:

1900

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0723

AC:

251

AN:

3472

East Asian (EAS)

AF:

0.165

AC:

855

AN:

5168

South Asian (SAS)

AF:

0.112

AC:

540

AN:

4816

European-Finnish (FIN)

AF:

0.0740

AC:

786

AN:

10620

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9182

AN:

67976

Other (OTH)

AF:

0.0979

AC:

207

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

694

1388

2083

2777

3471

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:

0.126

Hom.:

1005

Bravo

AF:

0.105

TwinsUK

AF:

0.135

AC:

500

ALSPAC

AF:

0.128

AC:

494

ESP6500AA

AF:

0.0354

AC:

ESP6500EA

AF:

0.140

AC:

446

ExAC

AF:

0.0969

AC:

2120

Asia WGS

AF:

0.122

AC:

423

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:2

Jan 13, 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

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

0.050

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0010

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.041

.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00052

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N

PhyloP100

-1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

0.38

N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T

Sift4G

Benign

0.089

T;T

Polyphen

0.0

B;B

Vest4

0.034

MPC

0.0096

ClinPred

0.00044

GERP RS

-2.6

Varity_R

0.034

gMVP

0.057

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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