chr6-65384473-G-GT

Variant summary

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

The NM_001142800.2(EYS):​c.1211dupA​(p.Asn404fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,601,590 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.05
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]

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 6-65384473-G-GT is Pathogenic according to our data. Variant chr6-65384473-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 636023.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
EYSNM_001142800.2 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 8/43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1
EYSNM_001292009.2 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 8/44 NP_001278938.1 Q5T1H1-3
EYSNM_001142801.2 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 8/12 NP_001136273.1 Q5T1H1-4
EYSNM_198283.2 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 7/10 NP_938024.1 Q5T1H1-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 8/435 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1
EYSENST00000370621.7 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 8/441 ENSP00000359655.3 Q5T1H1-3
EYSENST00000393380.6 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 8/121 ENSP00000377042.2 Q5T1H1-4
EYSENST00000342421.9 linkuse as main transcriptc.1211dupA p.Asn404fs frameshift_variant 6/91 ENSP00000341818.5 Q5T1H1-2

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151684
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000132
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248422
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134412
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000874
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:
0.000165
GnomAD4 exome
AF:
0.0000172
AC:
25
AN:
1449790
Hom.:
0
Cov.:
27
AF XY:
0.0000222
AC XY:
16
AN XY:
722198
show subpopulations
Gnomad4 AFR exome
AF:
0.000151
Gnomad4 AMR exome
AF:
0.0000674
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000127
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000544
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151800
Hom.:
1
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74194
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000132
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000378
Asia WGS
AF:
0.000290
AC:
1
AN:
3458

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Feb 01, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 17, 2021- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 25, 2024- -
Retinitis pigmentosa Pathogenic:2
Likely pathogenic, no assertion criteria providedresearchDepartment of Clinical Genetics, Copenhagen University Hospital, RigshospitaletApr 01, 2018- -
Pathogenic, no assertion criteria providedresearchSharon lab, Hadassah-Hebrew University Medical CenterJun 23, 2019- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 21, 2023This sequence change creates a premature translational stop signal (p.Asn404Lysfs*3) 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 (rs764163418, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 20375346). ClinVar contains an entry for this variant (Variation ID: 636023). For these reasons, this variant has been classified as Pathogenic. -
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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.

Other links and lift over

dbSNP: rs764163418; hg19: chr6-66094366; API