6-65384473-GT-GTT

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001142800.2(EYS):c.1211dupA(p.Asn404LysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,601,590 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.05

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-65384473-G-GT is Pathogenic according to our data. Variant chr6-65384473-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 636023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 8 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 8 of 44		NP_001278938.1	Q5T1H1-3
EYS	NM_001142801.2 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 8 of 12		NP_001136273.1	Q5T1H1-4
EYS	NM_198283.2 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 7 of 10		NP_938024.1	Q5T1H1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 8 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 8 of 44	1		ENSP00000359655.3	Q5T1H1-3
EYS	ENST00000393380.6 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 8 of 12	1		ENSP00000377042.2	Q5T1H1-4
EYS	ENST00000342421.9 link	c.1211dupA	p.Asn404LysfsTer3	frameshift_variant	Exon 6 of 9	1		ENSP00000341818.5	Q5T1H1-2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248422

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134412

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000874

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1449790

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

722198

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.0000674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000544

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151800

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000378

Asia WGS

AF:

0.000290

AC:

AN:

3458

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:3

Feb 01, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 17, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:2

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn404Lysfs*3) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs764163418, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 20375346). ClinVar contains an entry for this variant (Variation ID: 636023). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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