6-63720626-A-T

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.9405T>A(p.Tyr3135Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,354,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y3135Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: EYS NM_001142800.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.41

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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-63720626-A-T is Pathogenic according to our data. Variant chr6-63720626-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-63720626-A-T is described in Lovd as [Pathogenic]. Variant chr6-63720626-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.9405T>A	p.Tyr3135Ter	stop_gained	43/43	ENST00000503581.6
PHF3	NM_001370348.2	c.*6918A>T		3_prime_UTR_variant	16/16	ENST00000262043.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.9405T>A	p.Tyr3135Ter	stop_gained	43/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.9468T>A	p.Tyr3156Ter	stop_gained	44/44	1		P2
PHF3	ENST00000262043.8	c.*6918A>T		3_prime_UTR_variant	16/16	5	NM_001370348.2	P1
PHF3	ENST00000505138.1	c.363+9264A>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 2 AN: 124588 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000521

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: 0.000284

GnomAD4 exome AF: 0.0000140 AC: 19 AN: 1354866 Hom.: 0 Cov.: 28 AF XY: 0.0000180 AC XY: 12 AN XY: 665040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000206

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: 0.0000113

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2015	The Y3156X likely pathogenic variant in the EYS gene has been reported previously in the homozygous state in two unrelated families with autosomal recessive retinitis pigmentosa (Collin et al., 2008). This variant is predicted to cause loss of normal protein function through protein truncation. Furthermore, the Y3156X variant was not observed in approximately 2,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret Y3156X as a likely pathogenic variant -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Tyr3135*) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the EYS protein. This variant is present in population databases (rs137853190, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with EYS-related conditions (PMID: 18976725, 29159838, 30337596, 31074760). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.9468T>A;p.Y3156X. ClinVar contains an entry for this variant (Variation ID: 538). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

EYS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The EYS c.9405T>A variant is predicted to result in premature protein termination (p.Tyr3135*). This variant has been reported to be causative for autosomal recessive retinitis pigmentosa (Collin et al. 2008. PubMed ID: 18976725; Ezquerra-Inchausti et al. 2018. PubMed ID: 30337596; Messchaert et al. 2018. PubMed ID: 29159838). This variant is reported in 0.0050% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in EYS are expected to be pathogenic. This variant is interpreted as pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 10, 2018

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Tyr3135Ter variant in EYS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	0.42	A;A;A
Vest4		0.54
GERP RS		3.4

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: rs137853190; hg19: chr6-64430522;