6-63720626-A-T

Position:

chr6-63720626-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001142800.2(EYS):c.9405T>A(p.Tyr3135*) 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

EYS
NM_001142800.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 2.41

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]

EYS links:

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]

PHF3 links:

Genome browser will be placed here

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. Fraction of 0.00318 CDS is truncated, and there are 3 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	Protein	UniProt
EYS	NM_001142800.2 link	c.9405T>A	p.Tyr3135*	stop_gained	43/43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
PHF3	NM_001370348.2 link	c.*6918A>T		3_prime_UTR_variant	16/16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.9405T>A	p.Tyr3135*	stop_gained	43/43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.9468T>A	p.Tyr3156*	stop_gained	44/44	1		ENSP00000359655.3	Q5T1H1-3
PHF3	ENST00000262043.8 link	c.*6918A>T		3_prime_UTR_variant	16/16	5	NM_001370348.2	ENSP00000262043.4	Q92576-1
PHF3	ENST00000505138.1 link	c.361+9264A>T		intron_variant		3		ENSP00000421417.1	H0Y8L0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

124588

Hom.:

AF XY:

0.00

AC XY:

AN XY:

64614

show subpopulations

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:

AN:

1354866

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

665040

show subpopulations

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.:

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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+	-	- -
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	-	- -

Retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 10, 2018	- -

EYS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

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. -

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

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over