9-114408030-C-T

Position:

• chr9-114408030-C-T

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.1627-12G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,585,538 control chromosomes in the GnomAD database, including 43,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4077 hom., cov: 33)
  • Exomes 𝑓: 0.23 (39706 hom.)
• Consequence: WHRN NM_015404.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002423
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.179

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=-0.8).
• BP6: Variant 9-114408030-C-T is Benign according to our data. Variant chr9-114408030-C-T is described in ClinVar as [Benign]. Clinvar id is 45660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114408030-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.1627-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.1627-12G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_015404.4	P1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34495 AN: 151946 Hom.: 4079 Cov.: 33

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.199 AC: 41936 AN: 210840 Hom.: 4614 AF XY: 0.200 AC XY: 22657 AN XY: 113144

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.0647

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.229 AC: 328527 AN: 1433476 Hom.: 39706 Cov.: 32 AF XY: 0.228 AC XY: 161850 AN XY: 711018

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.0473

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.309

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.227 AC: 34495 AN: 152062 Hom.: 4077 Cov.: 33 AF XY: 0.228 AC XY: 16980 AN XY: 74316

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.0632

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.227

Alfa AF: 0.236 Hom.: 1203

Bravo AF: 0.211

Asia WGS AF: 0.116 AC: 404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2009	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Usher syndrome type 2D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0060
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: rs2274160; hg19: chr9-117170310; COSMIC: COSV54335246;