Variant chr9-114504718-CCCG-C details in Genebe, Genetics Data Aggregator

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

Genomes: 𝑓 0.00020 ( 1 hom., cov: 34)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

WHRN
NM_015404.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.11

Variant links:

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

WHRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_015404.4

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000204 (31/152270) while in subpopulation AFR AF= 0.000698 (29/41576). AF 95% confidence interval is 0.000498. There are 1 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.81_83delCGG	p.Gly28del	disruptive_inframe_deletion	Exon 1 of 12	ENST00000362057.4	NP_056219.3	Q9P202-1B9EGE6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WHRN	ENST00000362057.4 link	c.81_83delCGG	p.Gly28del	disruptive_inframe_deletion	Exon 1 of 12	1	NM_015404.4	ENSP00000354623.3	Q9P202-1
WHRN	ENST00000374057.3 link	c.81_83delCGG	p.Gly28del	disruptive_inframe_deletion	Exon 1 of 2	2		ENSP00000363170.3	Q9P202-2
WHRN	ENST00000673697.1 link	c.19_21delCGG		downstream_gene_variant				ENSP00000501152.1	A0A669KBA5

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1358808

Hom.:

AF XY:

0.0000209

AC XY:

AN XY:

670216

show subpopulations

Gnomad4 AFR exome

AF:

0.000528

Gnomad4 AMR exome

AF:

0.0000315

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000400

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000187

Gnomad4 OTH exome

AF:

0.000176

GnomAD4 genome

AF:

0.000204

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 19, 2017	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 17, 2016

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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