rs778030177

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001142800.2(EYS):c.1765A>G(p.Arg589Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000423 in 1,606,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R589K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 2.65

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-65334981-T-C is Pathogenic according to our data. Variant chr6-65334981-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551672.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=1}. Variant chr6-65334981-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EYS	NM_001142800.2 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	11/43	ENST00000503581.6
EYS	NM_198283.2 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant	10/10
EYS	NM_001292009.2 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	11/44
EYS	NM_001142801.2 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000342421.9 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant	9/9	1			Q5T1H1-2
EYS	ENST00000503581.6 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	11/43	5	NM_001142800.2	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	11/44	1		P2	Q5T1H1-3
EYS	ENST00000393380.6 linkuse as main transcript	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	11/12	1			Q5T1H1-4

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000962

AC:

AN:

249410

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000797

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1454324

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

723918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.000423

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000289

Gnomad4 OTH exome

AF:

0.0000832

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151772

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000756

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Macular dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 589 of the EYS protein (p.Arg589Gly). This variant is present in population databases (rs778030177, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 20237254, 30153090; Invitae). ClinVar contains an entry for this variant (Variation ID: 551672). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

0.0

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

0.032

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.51

T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Benign

-0.29

MutationTaster

Benign

0.99

N;N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.11

T;T;D;T

Sift4G

Uncertain

0.0020

D;D;T;T

Polyphen

0.96

D;.;.;D

Vest4

0.51

MVP

0.49

MPC

0.010

ClinPred

0.46

GERP RS

3.4

Varity_R

0.17

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.30

Position offset: -1

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