chr14-76491548-G-A
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_001379180.1(ESRRB):c.952G>A(p.Asp318Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,593,616 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001379180.1 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 35Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- nonsyndromic genetic hearing lossInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ESRRB | NM_001379180.1 | c.952G>A | p.Asp318Asn | missense_variant | Exon 6 of 7 | ENST00000644823.1 | NP_001366109.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ESRRB | ENST00000644823.1 | c.952G>A | p.Asp318Asn | missense_variant | Exon 6 of 7 | NM_001379180.1 | ENSP00000493776.1 |
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152280Hom.: 1 Cov.: 34 show subpopulations
GnomAD2 exomes AF: 0.000211 AC: 46AN: 217508 AF XY: 0.000180 show subpopulations
GnomAD4 exome AF: 0.000130 AC: 188AN: 1441218Hom.: 1 Cov.: 35 AF XY: 0.000108 AC XY: 77AN XY: 714718 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000256 AC: 39AN: 152398Hom.: 1 Cov.: 34 AF XY: 0.000174 AC XY: 13AN XY: 74524 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
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In silico analysis indicates that this missense variant does not alter protein structure/function; Reported in a patient with Meniere disease in published literature (PMID: 30828346); This variant is associated with the following publications: (PMID: 30828346) -
not specified Uncertain:1
The p.Asp297Asn variant in ESRRB has not been previously reported in individuals with hearing loss, but has been identified in 9/3358 Latino chromosomes and 5/3 4372 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs20134470). Although this variant has been seen in t he general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide s trong support for or against an impact to the protein. In summary, the clinical significance of the p.Asp297Asn variant is uncertain. -
Autosomal recessive nonsyndromic hearing loss 35 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at