rs143994166

Positions:

chr6-65402507-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001142800.2(EYS):c.1155T>A(p.Cys385Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,529,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

EYS
NM_001142800.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.204

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 6-65402507-A-T is Pathogenic according to our data. Variant chr6-65402507-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65402507-A-T is described in Lovd as [Pathogenic]. Variant chr6-65402507-A-T is described in Lovd as [Pathogenic]. Variant chr6-65402507-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EYS	NM_001142800.2 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	7/43	ENST00000503581.6
EYS	NM_001292009.2 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	7/44
EYS	NM_001142801.2 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	7/12
EYS	NM_198283.2 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	7/43	5	NM_001142800.2	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	7/44	1		P2	Q5T1H1-3
EYS	ENST00000393380.6 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	7/12	1			Q5T1H1-4
EYS	ENST00000342421.9 linkuse as main transcript	c.1155T>A	p.Cys385Ter	stop_gained	5/9	1			Q5T1H1-2

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000680

AC:

170

AN:

250020

Hom.:

AF XY:

0.000688

AC XY:

AN XY:

135170

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00644

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000264

AC:

364

AN:

1376844

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

190

AN XY:

689678

show subpopulations

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:

0.00559

Gnomad4 NFE exome

AF:

0.0000444

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000605

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000914

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00782

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000273

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000725

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:6

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001142800.1:c.1155T>A in the EYS gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. The EYS c.1155T>A (p.Cys385) variant results in a premature termination codon, predicted to cause a truncated or absent EYS protein due to nonsense mediated decay. This variant has been observed in a patient with retinitis pigmentosa, in a compound heterozygous state with c.8648_8655delCATGCAGA (p.Thr2883Lysfs4) (PMID: 28704921). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2018	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 10, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	-	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

This sequence change creates a premature translational stop signal (p.Cys385*) 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). This variant is present in population databases (rs143994166, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 27208204, 28704921). ClinVar contains an entry for this variant (Variation ID: 236447). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 12, 2024

Variant summary: EYS c.1155T>A (p.Cys385X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00068 in 250020 control chromosomes. c.1155T>A has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa (e.g., McGuigan_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28704921). ClinVar contains an entry for this variant (Variation ID: 236447). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.039

MutationTaster

Benign

1.0

A;A;A;A;A;A

Vest4

0.88

GERP RS

-0.87

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