rs1554565600

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001288575.2(EYA1):​c.-197A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

EYA1
NM_001288575.2 5_prime_UTR_premature_start_codon_gain

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.84
Variant links:
Genes affected
EYA1 (HGNC:3519): (EYA transcriptional coactivator and phosphatase 1) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may play a role in the developing kidney, branchial arches, eye, and ear. Mutations of this gene have been associated with branchiootorenal dysplasia syndrome, branchiootic syndrome, and sporadic cases of congenital cataracts and ocular anterior segment anomalies. A similar protein in mice can act as a transcriptional activator. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.106156796).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EYA1NM_000503.6 linkuse as main transcriptc.88A>G p.Ile30Val missense_variant 3/18 ENST00000340726.8 NP_000494.2 Q99502-1A0A024R813B3KXR1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EYA1ENST00000340726.8 linkuse as main transcriptc.88A>G p.Ile30Val missense_variant 3/181 NM_000503.6 ENSP00000342626.3 Q99502-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 14, 2017The p.Ile30Val variant in EYA1 has not been previously reported in individuals w ith hearing loss or in large population studies. Computational prediction tools and conservation analysis suggest that the variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, the clinical significance of the p.Ile30Val variant is uncertain. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 29, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T;T;T;.;.;T;T;.;.;.;.
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.93
.;.;.;D;D;.;D;D;D;D;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;L;L;L;.;L;L;.;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.020
N;.;N;N;N;.;.;.;.;.;N
REVEL
Benign
0.064
Sift
Benign
0.076
T;.;T;T;T;.;.;.;.;.;T
Sift4G
Benign
1.0
T;.;T;T;T;.;.;.;.;.;T
Polyphen
0.011
B;B;B;.;B;B;B;.;.;.;.
Vest4
0.14
MutPred
0.14
Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);.;.;.;Gain of phosphorylation at S34 (P = 0.1856);
MVP
0.42
MPC
0.21
ClinPred
0.59
D
GERP RS
1.8
Varity_R
0.055
gMVP
0.34

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: rs1554565600; hg19: chr8-72267053; COSMIC: COSV100378944; API