chr6-63726614-TGAAAG-T

Position:

chr6-63726614-TGAAAG-T

Variant summary

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

The NM_001142800.2(EYS):c.8133_8137del(p.Phe2712CysfsTer33) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000367 in 1,551,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.35

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 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-63726614-TGAAAG-T is Pathogenic according to our data. Variant chr6-63726614-TGAAAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-63726614-TGAAAG-T is described in Lovd as [Likely_pathogenic]. Variant chr6-63726614-TGAAAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.8133_8137del	p.Phe2712CysfsTer33	frameshift_variant	42/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2 linkuse as main transcript	c.8196_8200del	p.Phe2733CysfsTer33	frameshift_variant	43/44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.8133_8137del	p.Phe2712CysfsTer33	frameshift_variant	42/43	5	NM_001142800.2	ENSP00000424243	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.8196_8200del	p.Phe2733CysfsTer33	frameshift_variant	43/44	1		ENSP00000359655	P2	Q5T1H1-3
PHF3	ENST00000505138.1 linkuse as main transcript	c.363+15256_363+15260del		intron_variant		3		ENSP00000421417

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000586

AC:

AN:

153540

Hom.:

AF XY:

0.0000982

AC XY:

AN XY:

81444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000220

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000379

AC:

AN:

1399046

Hom.:

AF XY:

0.0000435

AC XY:

AN XY:

690044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000265

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000250

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:6

Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The EYS c.8133_8137del 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, PM3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 12, 2018	The EYS c.8133_8137delCTTTC; p.Phe2712fs variant (rs751629543), also known as c.8196_8200delCTTTC p.F2733Cfs*33 based on NM_001292009.1, is published in the medical literature in a family with autosomal recessive retinitis pigmentosa (Arai 2015). The variant is listed in the ClinVar database (Variation ID: 558163) and in the general population with an allele frequency of 0.006% (9/148188 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 5 nucleotides so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, this variant is predicted to cause loss of a critical functional domain (Hosono 2012). Considering available information, this variant is predicted to be pathogenic. References: Arai Y et al. Retinitis Pigmentosa with EYS Mutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations. J Ophthalmol. 2015;2015:819760 Hosono K et al. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population. PLoS One. 2012;7(2):e31036 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change creates a premature translational stop signal (p.Phe2712Cysfs*33) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 433 amino acid(s) of the EYS protein. This variant is present in population databases (rs751629543, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 26161267, 30153090). ClinVar contains an entry for this variant (Variation ID: 558163). This variant disrupts a region of the EYS protein in which other variant(s) (p.Thr3038Ilefs*4 and p.Asn3061Thrfs*3) have been determined to be pathogenic (PMID: 20333770, 21069908). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

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