8-71215630-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000503.6(EYA1):āc.1459T>Cā(p.Ser487Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 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 Pathogenic (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487L) has been classified as Likely benign.
Frequency
Consequence
NM_000503.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYA1 | NM_000503.6 | c.1459T>C | p.Ser487Pro | missense_variant | 15/18 | ENST00000340726.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYA1 | ENST00000340726.8 | c.1459T>C | p.Ser487Pro | missense_variant | 15/18 | 1 | NM_000503.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251282Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135788
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727192
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Melnick-Fraser syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 21, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EYA1 function (PMID: 11734542, 15802522, 16797546, 24489909). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EYA1 protein function. ClinVar contains an entry for this variant (Variation ID: 7940). This variant is also known as S454P. This missense change has been observed in individuals with branchiootorenal syndrome (PMID: 8566479, 9361030, 10464653; Invitae). This variant is present in population databases (rs121909200, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 487 of the EYA1 protein (p.Ser487Pro). - |
Branchiootorenal syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1997 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at