rs1173190962
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM5PP3_StrongBS2
The NM_004100.5(EYA4):c.1643C>T(p.Thr548Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T548R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004100.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYA4 | NM_004100.5 | c.1643C>T | p.Thr548Met | missense_variant | 18/20 | ENST00000355286.12 | |
TARID | NR_109982.1 | n.2285+12698G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYA4 | ENST00000355286.12 | c.1643C>T | p.Thr548Met | missense_variant | 18/20 | 1 | NM_004100.5 | P4 | |
TARID | ENST00000607033.5 | n.2261+12698G>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250990Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135630
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1459740Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726314
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74288
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 548 of the EYA4 protein (p.Thr548Met). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with EYA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 534387). 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 expected to disrupt EYA4 protein function with a positive predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at