rs1554163929

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001142800.2(EYS):​c.8678del​(p.Asn2893MetfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.06
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 33 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-63721352-AT-A is Pathogenic according to our data. Variant chr6-63721352-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517188.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EYSNM_001142800.2 linkuse as main transcriptc.8678del p.Asn2893MetfsTer25 frameshift_variant 43/43 ENST00000503581.6 NP_001136272.1
PHF3NM_001370348.2 linkuse as main transcriptc.*7647del 3_prime_UTR_variant 16/16 ENST00000262043.8 NP_001357277.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkuse as main transcriptc.8678del p.Asn2893MetfsTer25 frameshift_variant 43/435 NM_001142800.2 ENSP00000424243 A2Q5T1H1-1
EYSENST00000370621.7 linkuse as main transcriptc.8741del p.Asn2914MetfsTer25 frameshift_variant 44/441 ENSP00000359655 P2Q5T1H1-3
PHF3ENST00000262043.8 linkuse as main transcriptc.*7647del 3_prime_UTR_variant 16/165 NM_001370348.2 ENSP00000262043 P1Q92576-1
PHF3ENST00000505138.1 linkuse as main transcriptc.363+9993del intron_variant 3 ENSP00000421417

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 27, 2017The p.Asn2893MetfsX25 (NM_001142800.1 c.8678delA) variant in EYS has not been pr eviously reported in individuals with retinitis pigmentosa. Data from large popu lation studies is of insufficient coverage at this location to assess the freque ncy of this variant. This variant is predicted to cause a frameshift, which alte rs the protein?s amino acid sequence beginning at position 2893 and leads to a p remature termination codon 25 amino acids downstream. This alteration is then pr edicted to lead to a truncated or absent protein. Biallelic loss of function of the EYS gene is an established disease mechanism in retinitis pigmentosa. In sum mary, although additional studies are required to fully establish its clinical s ignificance, the p.Asn2893MetfsX25 variant is likely pathogenic for retinitis pi gmentosa in an autosomal recessive manner based upon its predicted functional im pact. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554163929; hg19: chr6-64431248; API