rs624851

Variant summary

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

The NM_001142800.2(EYS):c.4256T>C(p.Leu1419Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,550,802 control chromosomes in the GnomAD database, including 402,452 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

Frequency

Genomes: 𝑓 0.77 ( 45597 hom., cov: 30)

Exomes 𝑓: 0.71 ( 356855 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.05

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=8.1337487E-7).

BP6

Variant 6-64591611-A-G is Benign according to our data. Variant chr6-64591611-A-G is described in ClinVar as [Benign]. Clinvar id is 93611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64591611-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.934 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.4256T>C	p.Leu1419Ser	missense_variant	26/43	ENST00000503581.6
EYS	NM_001292009.2 linkuse as main transcript	c.4256T>C	p.Leu1419Ser	missense_variant	26/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.4256T>C	p.Leu1419Ser	missense_variant	26/43	5	NM_001142800.2	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.4256T>C	p.Leu1419Ser	missense_variant	26/44	1		P2	Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.767

AC:

116364

AN:

151782

Hom.:

45533

Cov.:

show subpopulations

Gnomad AFR

AF:

0.942

Gnomad AMI

AF:

0.653

Gnomad AMR

AF:

0.745

Gnomad ASJ

AF:

0.650

Gnomad EAS

AF:

0.666

Gnomad SAS

AF:

0.772

Gnomad FIN

AF:

0.702

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.692

Gnomad OTH

AF:

0.711

GnomAD3 exomes

AF:

0.729

AC:

111796

AN:

153440

Hom.:

41130

AF XY:

0.728

AC XY:

59254

AN XY:

81400

show subpopulations

Gnomad AFR exome

AF:

0.950

Gnomad AMR exome

AF:

0.777

Gnomad ASJ exome

AF:

0.642

Gnomad EAS exome

AF:

0.659

Gnomad SAS exome

AF:

0.778

Gnomad FIN exome

AF:

0.704

Gnomad NFE exome

AF:

0.692

Gnomad OTH exome

AF:

0.712

GnomAD4 exome

AF:

0.713

AC:

996812

AN:

1398902

Hom.:

356855

Cov.:

AF XY:

0.713

AC XY:

492035

AN XY:

689970

show subpopulations

Gnomad4 AFR exome

AF:

0.948

Gnomad4 AMR exome

AF:

0.775

Gnomad4 ASJ exome

AF:

0.648

Gnomad4 EAS exome

AF:

0.699

Gnomad4 SAS exome

AF:

0.778

Gnomad4 FIN exome

AF:

0.709

Gnomad4 NFE exome

AF:

0.701

Gnomad4 OTH exome

AF:

0.715

GnomAD4 genome

AF:

0.767

AC:

116486

AN:

151900

Hom.:

45597

Cov.:

AF XY:

0.766

AC XY:

56826

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.942

Gnomad4 AMR

AF:

0.745

Gnomad4 ASJ

AF:

0.650

Gnomad4 EAS

AF:

0.666

Gnomad4 SAS

AF:

0.772

Gnomad4 FIN

AF:

0.702

Gnomad4 NFE

AF:

0.692

Gnomad4 OTH

AF:

0.714

Alfa

AF:

0.702

Hom.:

56583

Bravo

AF:

0.777

TwinsUK

AF:

0.697

AC:

2586

ALSPAC

AF:

0.708

AC:

2728

ESP6500AA

AF:

0.942

AC:

1304

ESP6500EA

AF:

0.701

AC:

2232

ExAC

AF:

0.737

AC:

15406

Asia WGS

AF:

0.745

AC:

2590

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Retinitis pigmentosa 25

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Mar 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Retinitis pigmentosa

Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

0.087

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

Cadd

Benign

6.1

Dann

Benign

0.19

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.19

T;T

MetaRNN

Benign

8.1e-7

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.21

PROVEAN

Benign

0.12

N;N

REVEL

Benign

0.25

Sift

Benign

0.034

D;T

Sift4G

Benign

0.32

T;T

Polyphen

0.010

B;B

Vest4

0.029

MPC

0.0094

ClinPred

0.0043

GERP RS

0.38

Varity_R

0.037

gMVP

0.045

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