rs371408686
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_000503.6(EYA1):c.1426G>A(p.Asp476Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
EYA1
NM_000503.6 missense
NM_000503.6 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 7.82
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 Likely_benign. Variant got -2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.856
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EYA1 | NM_000503.6 | c.1426G>A | p.Asp476Asn | missense_variant | 15/18 | ENST00000340726.8 | NP_000494.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYA1 | ENST00000340726.8 | c.1426G>A | p.Asp476Asn | missense_variant | 15/18 | 1 | NM_000503.6 | ENSP00000342626.3 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251276Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135796
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727224
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
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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 submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 22, 2015 | The p.Asp476Asn variant in EYA1 has not been previously reported in individuals with hearing loss, but has been identified in 1/67644 of European chromosomes an d in 1/10580 of African chromosomes by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs371408686). Although this variant has bee n seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools do not provide strong support f or or against an impact to the protein. In summary, the clinical significance of the p.Asp476Asn variant is uncertain. - |
Branchiootic syndrome 1;C3714941:Otofaciocervical syndrome 1;C4551702:Branchiootorenal syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;.;.;.;D;D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;.;D;D;D;.;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M;.;.;.;M;M;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D;D;D;.;.;.;.;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;D;D;.;.;.;.;.;D;D
Sift4G
Uncertain
D;.;D;D;D;D;.;.;.;.;.;D;D
Polyphen
D;D;D;.;D;D;D;D;.;.;.;.;.
Vest4
MVP
MPC
0.31
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at