rs869312188

Positions:

• chr6-63720752-A-ACC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001142800.2(EYS):​c.9278_9279insGG​(p.Arg3094ValfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,398,352 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: 0.0000064 (0 hom.)
• Consequence: EYS NM_001142800.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.24

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 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 6-63720752-A-ACC is Pathogenic according to our data. Variant chr6-63720752-A-ACC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.9278_9279insGG	p.Arg3094ValfsTer4	frameshift_variant	43/43	ENST00000503581.6	NP_001136272.1
PHF3	NM_001370348.2	c.*7045_*7046dup		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	c.9278_9279insGG	p.Arg3094ValfsTer4	frameshift_variant	43/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.9341_9342insGG	p.Arg3115ValfsTer4	frameshift_variant	44/44	1		ENSP00000359655	P2
PHF3	ENST00000262043.8	c.*7045_*7046dup		3_prime_UTR_variant	16/16	5	NM_001370348.2	ENSP00000262043	P1
PHF3	ENST00000505138.1	c.363+9391_363+9392dup		intron_variant		3		ENSP00000421417

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000644 AC: 9 AN: 1398352 Hom.: 0 Cov.: 32 AF XY: 0.00000870 AC XY: 6 AN XY: 689678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000835

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 14, 2020

This sequence change results in a premature translational stop signal in the EYS gene (p.Arg3094Valfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the EYS protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the EYS protein. Other variant(s) that disrupt this region (p.Tyr3135*) have been determined to be pathogenic (PMID: 18976725, 31074760, 29159838, 30337596). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with retinitis pigmentosa (PMID: 22581970). ClinVar contains an entry for this variant (Variation ID: 224759). This variant is not present in population databases (ExAC no frequency). -

Retinitis pigmentosa 25 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 07, 2020

- -

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Jan 30, 2015

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 31, 2023

Variant summary: EYS c.9277_9278dupGG (p.Arg3094ValfsX4) is located in exon 43 (i.e. in the last exon), and results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, that removes a part of the fifth laminin G domain (amino acids 2975-3165; IPR001791). Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 155724 control chromosomes (gnomAD). c.9277_9278dupGG has been reported in the literature in at least one compound heterozygous individual affected with inherited retinal disease (O'Sullivan_2012, Ellingford_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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: rs869312188; hg19: chr6-64430648;