rs770748359

Positions:

chr6-63720735-ACGATATTTAC-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001142800.2(EYS):c.9286_9295del(p.Val3096LeufsTer28) variant causes a frameshift change. The variant allele was found at a frequency of 0.000105 in 1,549,352 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 6.11

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:

PHF3 (HGNC:8921): (PHD finger protein 3) This gene encodes a member of a PHD finger-containing gene family. This gene may function as a transcription factor and may be involved in glioblastomas development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

PHF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-63720735-ACGATATTTAC-A is Pathogenic according to our data. Variant chr6-63720735-ACGATATTTAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-63720735-ACGATATTTAC-A is described in Lovd as [Pathogenic]. Variant chr6-63720735-ACGATATTTAC-A is described in Lovd as [Pathogenic]. Variant chr6-63720735-ACGATATTTAC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.9286_9295del	p.Val3096LeufsTer28	frameshift_variant	43/43	ENST00000503581.6	NP_001136272.1
PHF3	NM_001370348.2 linkuse as main transcript	c.7029_7038del		3_prime_UTR_variant	16/16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.9286_9295del	p.Val3096LeufsTer28	frameshift_variant	43/43	5	NM_001142800.2	ENSP00000424243	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.9349_9358del	p.Val3117LeufsTer28	frameshift_variant	44/44	1		ENSP00000359655	P2	Q5T1H1-3
PHF3	ENST00000262043.8 linkuse as main transcript	c.7029_7038del		3_prime_UTR_variant	16/16	5	NM_001370348.2	ENSP00000262043	P1	Q92576-1
PHF3	ENST00000505138.1 linkuse as main transcript	c.363+9375_363+9384del		intron_variant		3		ENSP00000421417

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

154606

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

81822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00263

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000669

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.000102

AC:

143

AN:

1397308

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

689012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00411

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000195

Gnomad4 OTH exome

AF:

0.000311

GnomAD4 genome

AF:

0.000125

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000400

Hom.:

Bravo

AF:

0.000110

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2023	Frameshift variant predicted to result in abnormal protein length as the last 49 amino acids are replaced with 27 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 31980526, 26261414, 24474277, 31589614, 32037395, 29550188) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Val3096Leufs28) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the EYS protein. This variant is present in population databases (rs770748359, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with EYS-related conditions (PMID: 24474277, 26261414, 29550188). ClinVar contains an entry for this variant (Variation ID: 289906). This variant disrupts the C-terminus of the EYS protein. Other variant(s) that disrupt this region (p.Tyr3135, p.Asn3123Lysfs*3) have been observed in individuals with EYS-related conditions (PMID: 18976725, 20333770). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Retinitis pigmentosa 25

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The EYS c.9286_9295del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP1. Based on this evidence we have classified this variant as Likely Pathogenic. -

Retinitis pigmentosa

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Val3096LeufsTer28 variant in EYS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

EYS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2024

The EYS c.9286_9295del10 variant is predicted to result in a frameshift and premature protein termination (p.Val3096Leufs*28). This variant has been reported in the homozygous or compound heterozygous state in several individuals with retinitis pigmentosa (see for example, Beryozkin et al. 2014. PubMed ID: 24474277; Zampaglione et al. 2020. PubMed ID: 32037395; Tracewska et al 2021. PubMed ID: 34321860; Zampaglione et al. 2021. PubMed ID: 34906470; Weisschuh et al. 2024. PubMed ID: 37734845; Sengillo et al. 2018. PubMed ID: 29550188). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in EYS are expected to be pathogenic. This variant is interpreted as pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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