rs751629543

chr6-63726614-TGAAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.35

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]

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]

ACMG classification

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 146 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	UniProt
EYS	NM_001142800.2	c.8133_8137del	p.Phe2712CysfsTer33	frameshift_variant	42/43	ENST00000503581.6
EYS	NM_001292009.2	c.8196_8200del	p.Phe2733CysfsTer33	frameshift_variant	43/44

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152002 Hom.: 0 Cov.: 32

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: 9 AN: 153540 Hom.: 0 AF XY: 0.0000982 AC XY: 8 AN XY: 81444

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: 53 AN: 1399046 Hom.: 0 AF XY: 0.0000435 AC XY: 30 AN XY: 690044

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: 4 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74240

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

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2023	- -
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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
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

Invitae

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs751629543; hg19: chr6-64436507;