rs764163418

Positions:

• chr6-65384473-GT-G
• chr6-65384473-GT-GTT

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.1211del​(p.Asn404ThrfsTer17) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EYS NM_001142800.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-65384473-GT-G is Pathogenic according to our data. Variant chr6-65384473-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 438192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65384473-GT-G is described in Lovd as [Pathogenic]. Variant chr6-65384473-GT-G is described in Lovd as [Likely_pathogenic]. Variant chr6-65384473-GT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	8/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	8/44		NP_001278938.1
EYS	NM_001142801.2	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	8/12		NP_001136273.1
EYS	NM_198283.2	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	7/10		NP_938024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	8/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	8/44	1		ENSP00000359655	P2
EYS	ENST00000393380.6	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	8/12	1		ENSP00000377042
EYS	ENST00000342421.9	c.1211del	p.Asn404ThrfsTer17	frameshift_variant	6/9	1		ENSP00000341818

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449818 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 722204

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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

Jun 30, 2021

ClinVar contains an entry for this variant (Variation ID: 438192). This premature translational stop signal has been observed in individual(s) with clinical features of EYS-related conditions (PMID: 28041643). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn404Thrfs*17) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 25 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 13, 2022

- -

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764163418; hg19: chr6-66094366;