chr6-64813377-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001142800.2(EYS):c.3443+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000429 in 1,538,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

EYS
NM_001142800.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 5.76

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

EYS-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
retinitis pigmentosa 25
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

EYS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 10, offset of 22, new splice context is: caaGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 6-64813377-C-A is Pathogenic according to our data. Variant chr6-64813377-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.3443+1G>T		splice_donor_variant, intron_variant	Intron 22 of 42	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.3443+1G>T		splice_donor_variant, intron_variant	Intron 22 of 43		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 link	c.3443+1G>T		splice_donor_variant, intron_variant	Intron 22 of 42	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 link	c.3443+1G>T		splice_donor_variant, intron_variant	Intron 22 of 43	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

146414

AF XY:

0.0000128

show subpopulations

Gnomad AFR exome

AF:

0.000141

Gnomad AMR exome

AF:

0.0000899

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000252

AC:

AN:

1386652

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

683394

show subpopulations

African (AFR)

AF:

0.000422

AC:

AN:

30816

American (AMR)

AF:

0.000118

AC:

AN:

33976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24908

East Asian (EAS)

AF:

0.00

AC:

AN:

35088

South Asian (SAS)

AF:

0.00

AC:

AN:

76508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073038

Other (OTH)

AF:

0.000313

AC:

AN:

57490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.000676

AC:

AN:

41392

American (AMR)

AF:

0.000197

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:5

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The EYS c.3443+1G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic. -

Mar 06, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 25, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 24, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 22 of the EYS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs373441420, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with retinal disease (PMID: 20237254, 29550188; internal data). ClinVar contains an entry for this variant (Variation ID: 195665). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26667666, 29550188, 36819107, 34906470, 32037395, 38219857, 39676705, 31964843, 36284670, 25097241, 39588395, 31736247) -

Retinitis pigmentosa

Pathogenic:3

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The c.3443+1G>T 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, PP3. 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. -

Feb 04, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: EYS c.3443+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of EYS function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 146414 control chromosomes. c.3443+1G>T has been reported in the literature in individuals affected with Retinitis Pigmentosa (examples: Wang_2014, Ge_2015, Sengillo_2018 Santos_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25097241, 36196406, 26667666, 29550188). ClinVar contains an entry for this variant (Variation ID: 195665). Based on the evidence outlined above, the variant was classified as pathogenic. -

EYS-related disorder

Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EYS c.3443+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous states in individual with retinitis pigmentosa (for example, Wang et al. 2014. PubMed ID: 25097241; Ge et al. 2015. PubMed ID: 26667666; Sengillo et al. 2018. PubMed ID: 29550188). This variant is reported in 0.057% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in EYS are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/195665). Given the evidence, we interpret c.3443+1G>T as pathogenic. -

Retinal dystrophy

Pathogenic:1

Jul 24, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.85

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.90

PhyloP100

5.8

GERP RS

4.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -21

DS_DL_spliceai

1.0

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over