rs764229134

Positions:

• chr6-63726595-ATG-A

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.8155_8156delCA​(p.His2719fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000114 in 1,399,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: EYS NM_001142800.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.83

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 60 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-63726595-ATG-A is Pathogenic according to our data. Variant chr6-63726595-ATG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-63726595-ATG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.8155_8156delCA	p.His2719fs	frameshift_variant	42/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.8218_8219delCA	p.His2740fs	frameshift_variant	43/44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.8155_8156delCA	p.His2719fs	frameshift_variant	42/43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.8218_8219delCA	p.His2740fs	frameshift_variant	43/44	1		ENSP00000359655.3
PHF3	ENST00000505138.1	c.361+15237_361+15238delGT		intron_variant		3		ENSP00000421417.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000651 AC: 1 AN: 153622 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000232

GnomAD4 exome AF: 0.0000114 AC: 16 AN: 1399044 Hom.: 0 AF XY: 0.0000130 AC XY: 9 AN XY: 690032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 01, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2023

This variant is present in population databases (rs764229134, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.His2719Tyrfs*27) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 426 amino acid(s) of the EYS protein. This premature translational stop signal has been observed in individuals with recessive retinitis pigmentosa (PMID: 20375346). ClinVar contains an entry for this variant (Variation ID: 554682). This variant is also known as c.8218_8219delCA. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the EYS protein in which other variant(s) (p.Tyr2935*) have been determined to be pathogenic (PMID: 22363543, 24652164, 28763560). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs764229134; hg19: chr6-64436488;