14-76498322-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_001379180.1(ESRRB):c.1229C>T(p.Thr410Met) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,570,520 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001379180.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ESRRB | NM_001379180.1 | c.1229C>T | p.Thr410Met | missense_variant | Exon 7 of 7 | ENST00000644823.1 | NP_001366109.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ESRRB | ENST00000644823.1 | c.1229C>T | p.Thr410Met | missense_variant | Exon 7 of 7 | NM_001379180.1 | ENSP00000493776.1 |
Frequencies
GnomAD3 genomes AF: 0.000146 AC: 22AN: 150560Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000122 AC: 30AN: 246784Hom.: 0 AF XY: 0.0000894 AC XY: 12AN XY: 134246
GnomAD4 exome AF: 0.000118 AC: 167AN: 1419816Hom.: 1 Cov.: 35 AF XY: 0.000112 AC XY: 79AN XY: 706760
GnomAD4 genome AF: 0.000146 AC: 22AN: 150704Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 13AN XY: 73676
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Thr389Met variant in ESRRB has been reported in one Turkish individual wit h prelingual sensorineural hearing loss who did not have a second ESRRB variant (Collin 2008). This variant has also been identified in 5/6176 Finnish chromosom es and 22/114190 total chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs201714970). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Of note, 2 mamm als (chinchilla and bushed-tail rat) have a methionine (Met) at this position de spite high nearby amino acid sequence conservation. In summary, while the clinic al significance of the p.Thr389Met variant is uncertain, available data suggest that it is more likely to be benign. -
not provided Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 389 of the ESRRB protein (p.Thr389Met). This variant is present in population databases (rs201714970, gnomAD 0.04%). This missense change has been observed in individual(s) with deafness (PMID: 18179891). ClinVar contains an entry for this variant (Variation ID: 504570). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at