6-63720617-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_001142800.2(EYS):ā€‹c.9414T>Gā€‹(p.Asp3138Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000696 in 1,493,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000070 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.02
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a domain Laminin G-like 5 (size 190) in uniprot entity EYS_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_001142800.2
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.013729215).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EYSNM_001142800.2 linkc.9414T>G p.Asp3138Glu missense_variant Exon 43 of 43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1
PHF3NM_001370348.2 linkc.*6909A>C 3_prime_UTR_variant Exon 16 of 16 ENST00000262043.8 NP_001357277.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkc.9414T>G p.Asp3138Glu missense_variant Exon 43 of 43 5 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1
EYSENST00000370621.7 linkc.9477T>G p.Asp3159Glu missense_variant Exon 44 of 44 1 ENSP00000359655.3 Q5T1H1-3
PHF3ENST00000262043.8 linkc.*6909A>C 3_prime_UTR_variant Exon 16 of 16 5 NM_001370348.2 ENSP00000262043.4 Q92576-1
PHF3ENST00000505138.1 linkc.361+9255A>C intron_variant Intron 3 of 4 3 ENSP00000421417.1 H0Y8L0

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152140
Hom.:
0
Cov.:
32
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:
0.00173
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000218
AC:
25
AN:
114426
Hom.:
0
AF XY:
0.000238
AC XY:
14
AN XY:
58778
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00203
Gnomad SAS exome
AF:
0.000500
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000701
AC:
94
AN:
1341268
Hom.:
0
Cov.:
28
AF XY:
0.0000746
AC XY:
49
AN XY:
657218
show subpopulations
Gnomad4 AFR exome
AF:
0.0000341
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00153
Gnomad4 SAS exome
AF:
0.000499
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000720
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00173
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000121
ExAC
AF:
0.0000831
AC:
2
Asia WGS
AF:
0.000289
AC:
1
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 3138 of the EYS protein (p.Asp3138Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 29641573). ClinVar contains an entry for this variant (Variation ID: 964717). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 03, 2015
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Retinitis pigmentosa 25 Uncertain:1
Aug 05, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.042
.;T
Eigen
Benign
-0.017
Eigen_PC
Benign
0.040
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.44
T;T
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.014
T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
1.2
.;L
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.88
N;N
REVEL
Benign
0.24
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.038
D;D
Polyphen
0.58
P;P
Vest4
0.30
MutPred
0.41
.;Gain of catalytic residue at D3159 (P = 0.087);
MVP
0.49
MPC
0.010
ClinPred
0.11
T
GERP RS
3.3
Varity_R
0.14
gMVP
0.16

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: rs374161234; hg19: chr6-64430513; COSMIC: COSV65481307; API