rs398123576

Positions:

• chr6-63721622-A-AT

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.8408_8409insA​(p.Asn2803LysfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,399,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: EYS NM_001142800.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.788

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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 45 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-63721622-A-AT is Pathogenic according to our data. Variant chr6-63721622-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 93622.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.8408_8409insA	p.Asn2803LysfsTer9	frameshift_variant	43/43	ENST00000503581.6	NP_001136272.1
PHF3	NM_001370348.2	c.*7917dup		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.8408_8409insA	p.Asn2803LysfsTer9	frameshift_variant	43/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.8471_8472insA	p.Asn2824LysfsTer9	frameshift_variant	44/44	1		ENSP00000359655	P2
PHF3	ENST00000262043.8	c.*7917dup		3_prime_UTR_variant	16/16	5	NM_001370348.2	ENSP00000262043	P1
PHF3	ENST00000505138.1	c.363+10263dup		intron_variant		3		ENSP00000421417

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000191 AC: 3 AN: 157218 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83090

Gnomad AFR exome AF: 0.000124

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: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 47 AN: 1399074 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 19 AN XY: 690050

Gnomad4 AFR exome AF: 0.0000317

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: 0.0000417

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	This sequence change creates a premature translational stop signal (p.Asn2803Lysfs*9) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 342 amino acid(s) of the EYS protein. This variant is present in population databases (rs398123576, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 23591405, 28704921; Invitae). ClinVar contains an entry for this variant (Variation ID: 93622). This variant disrupts a region of the EYS protein in which other variant(s) (p.Val3096Leufs*28) have been determined to be pathogenic (PMID: 24474277, 26261414, 29550188). 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. -

Retinitis pigmentosa 25 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 17, 2018

- -

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: rs398123576; hg19: chr6-64431518;