9-114426434-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015404.4(WHRN):c.964-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,612,952 control chromosomes in the GnomAD database, including 74,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7470 hom., cov: 33)
  • Exomes 𝑓: 0.30 (67272 hom.)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.643

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-114426434-T-C is Benign according to our data. Variant chr9-114426434-T-C is described in ClinVar as [Benign]. Clinvar id is 1238923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114426434-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.964-21A>G		intron_variant		ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.964-21A>G		intron_variant		1	NM_015404.4	P1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47540 AN: 151868 Hom.: 7449 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.330 AC: 81254 AN: 246114 Hom.: 14068 AF XY: 0.323 AC XY: 43129 AN XY: 133414

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.468

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.384

Gnomad SAS exome AF: 0.350

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.300 AC: 438246 AN: 1460966 Hom.: 67272 Cov.: 33 AF XY: 0.300 AC XY: 218253 AN XY: 726756

Gnomad4 AFR exome AF: 0.332

Gnomad4 AMR exome AF: 0.457

Gnomad4 ASJ exome AF: 0.284

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.352

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.313 AC: 47611 AN: 151986 Hom.: 7470 Cov.: 33 AF XY: 0.313 AC XY: 23281 AN XY: 74300

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.370

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.374

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.317

Alfa AF: 0.308 Hom.: 3584

Bravo AF: 0.323

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	8.8
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs2274163; hg19: chr9-117188714; COSMIC: COSV54328529; COSMIC: COSV54328529;