chr9-114504718-CCCG-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP3BS1_Supporting
The NM_015404.4(WHRN):c.81_83delCGG(p.Gly28del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,511,078 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_015404.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WHRN | ENST00000362057.4 | c.81_83delCGG | p.Gly28del | disruptive_inframe_deletion | Exon 1 of 12 | 1 | NM_015404.4 | ENSP00000354623.3 | ||
WHRN | ENST00000374057.3 | c.81_83delCGG | p.Gly28del | disruptive_inframe_deletion | Exon 1 of 2 | 2 | ENSP00000363170.3 | |||
WHRN | ENST00000673697.1 | c.*19_*21delCGG | downstream_gene_variant | ENSP00000501152.1 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152164Hom.: 1 Cov.: 34
GnomAD4 exome AF: 0.0000228 AC: 31AN: 1358808Hom.: 0 AF XY: 0.0000209 AC XY: 14AN XY: 670216
GnomAD4 genome AF: 0.000204 AC: 31AN: 152270Hom.: 1 Cov.: 34 AF XY: 0.000215 AC XY: 16AN XY: 74454
ClinVar
Submissions by phenotype
not provided Uncertain:2
The p.Gly28del variant (rs757435431) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 228565). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.008% (identified in 11 out of 132,060 chromosomes). The p.Gly28del variant is an in-frame contraction of a poly-glycine repeat and is in a region not conserved among species, suggesting this deleted amino acid is not critical for WHRN protein structure/function. However, based on the available information, the clinical significance of the p.Gly28del variant cannot be determined with certainty. -
This variant, c.81_83del, results in the deletion of 1 amino acid(s) of the WHRN protein (p.Gly29del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 228565). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Gly29del vari ant in DFNB31 has been previously reported in 1 individual with hearing loss by our laboratory; however, a variant affecting the remaining copy of DFNB31 was no t identified. This variant has been identified in 1/356 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 757435431); however, this frequency is not high enough to rule out a pathogenic role. The glycine (Gly) residue at position 29 lies in a poly-glycine tract with in the DFNB31 protein, and this variant is predicted to result in an in-frame de letion of a single glycine residue (Gly) within this poly-glycine tract. The reg ion encompassing this poly-glycine tract is not well conserved across species an d several species have an in-frame glycine deletion at this position or nearby g lycine positions, suggesting the variant may not impact the protein. However, th is information is insufficient to rule out pathogenicity. In summary, while the clinical significance of the p.Gly29del variant is uncertain, the conservation d ata suggests that it is more likely to be benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at