NM_001142800.2:c.4549A>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.4549A>G(p.Ser1517Gly) 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 1,550,952 control chromosomes in the GnomAD database, including 13,821 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 (★★).

Frequency

Genomes: 𝑓 0.10 ( 915 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12906 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.326

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=0.003168881).

BP6

Variant 6-64591318-T-C is Benign according to our data. Variant chr6-64591318-T-C is described in ClinVar as Benign. ClinVar VariationId is 93614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.4549A>G	p.Ser1517Gly	missense_variant	Exon 26 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.4549A>G	p.Ser1517Gly	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.4549A>G	p.Ser1517Gly	missense_variant	Exon 26 of 43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 link	c.4549A>G	p.Ser1517Gly	missense_variant	Exon 26 of 44	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15330

AN:

152046

Hom.:

918

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0365

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.0721

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0738

Gnomad MID

AF:

0.0701

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.0983

GnomAD2 exomes

AF:

0.119

AC:

18248

AN:

153770

AF XY:

0.119

show subpopulations

Gnomad AFR exome

AF:

0.0305

Gnomad AMR exome

AF:

0.136

Gnomad ASJ exome

AF:

0.0821

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:

185052

AN:

1398788

Hom.:

12906

Cov.:

AF XY:

0.132

AC XY:

91032

AN XY:

689948

show subpopulations

African (AFR)

AF:

0.0303

AC:

956

AN:

31584

American (AMR)

AF:

0.135

AC:

4827

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0796

AC:

2004

AN:

25168

East Asian (EAS)

AF:

0.145

AC:

5170

AN:

35732

South Asian (SAS)

AF:

0.105

AC:

8285

AN:

79224

European-Finnish (FIN)

AF:

0.0808

AC:

3979

AN:

49266

Middle Eastern (MID)

AF:

0.0574

AC:

327

AN:

5698

European-Non Finnish (NFE)

AF:

0.141

AC:

152303

AN:

1078440

Other (OTH)

AF:

0.124

AC:

7201

AN:

57972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

9519

19038

28558

38077

47596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5578

11156

16734

22312

27890

<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:

15325

AN:

152164

Hom.:

915

Cov.:

AF XY:

0.0991

AC XY:

7374

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0364

AC:

1514

AN:

41568

American (AMR)

AF:

0.124

AC:

1895

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.0721

AC:

250

AN:

3468

East Asian (EAS)

AF:

0.164

AC:

846

AN:

5152

South Asian (SAS)

AF:

0.112

AC:

540

AN:

4820

European-Finnish (FIN)

AF:

0.0738

AC:

783

AN:

10616

Middle Eastern (MID)

AF:

0.0685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.135

AC:

9179

AN:

67984

Other (OTH)

AF:

0.0972

AC:

205

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

687

1374

2061

2748

3435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.121

Hom.:

2713

Bravo

AF:

0.105

TwinsUK

AF:

0.133

AC:

495

ALSPAC

AF:

0.127

AC:

489

ESP6500AA

AF:

0.0354

AC:

ESP6500EA

AF:

0.140

AC:

446

ExAC

AF:

0.0969

AC:

2109

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 provided

Benign:3

Aug 11, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in ARRP panel(s). -

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

- -

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

0.058

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.10

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.042

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.19

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N

PhyloP100

-0.33

PrimateAI

Benign

0.22

PROVEAN

Benign

0.20

N;N

REVEL

Benign

0.11

Sift

Benign

0.75

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0010

B;B

Vest4

0.028

MPC

0.0098

ClinPred

0.00027

GERP RS

2.0

Varity_R

0.027

gMVP

0.019

Mutation Taster

=100/0

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