chr2-26477421-C-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1
The NM_194248.3(OTOF):c.2401G>T(p.Glu801*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00657 in 1,586,870 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_194248.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0329 AC: 5000AN: 152140Hom.: 264 Cov.: 32
GnomAD3 exomes AF: 0.00855 AC: 1762AN: 206140Hom.: 92 AF XY: 0.00619 AC XY: 685AN XY: 110670
GnomAD4 exome AF: 0.00377 AC: 5411AN: 1434612Hom.: 270 Cov.: 33 AF XY: 0.00322 AC XY: 2287AN XY: 710830
GnomAD4 genome AF: 0.0329 AC: 5013AN: 152258Hom.: 265 Cov.: 32 AF XY: 0.0321 AC XY: 2392AN XY: 74450
ClinVar
Submissions by phenotype
not specified Benign:2
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant summary: OTOF c.2401G>T (p.Glu801X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.012 in 237518 control chromosomes, predominantly at a frequency of 0.12 within the African or African-American subpopulation in the gnomAD database, including 139 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 107 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2401G>T in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 9 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign and likely benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:2
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Autosomal recessive nonsyndromic hearing loss 9 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at