rs4979386

Variant names:

• chr9-114424312-T-A
• rs4979386
• NM_015404.4:c.1416+22A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.1416+22A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,610,756 control chromosomes in the GnomAD database, including 47,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3678 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43338 hom.)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.645
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• autosomal recessive nonsyndromic hearing loss 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-114424312-T-A is Benign according to our data. Variant chr9-114424312-T-A is described in ClinVar as Benign. ClinVar VariationId is 1230190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.1416+22A>T		intron_variant	Intron 6 of 11	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.1416+22A>T		intron_variant	Intron 6 of 11	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30636 AN: 151904 Hom.: 3666 Cov.: 32

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.264 AC: 66122 AN: 250498 AF XY: 0.259

Gnomad AFR exome AF: 0.0696

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.237 AC: 345359 AN: 1458730 Hom.: 43338 Cov.: 33 AF XY: 0.237 AC XY: 172334 AN XY: 725726

African (AFR) AF: 0.0634 AC: 2117 AN: 33392

American (AMR) AF: 0.416 AC: 18606 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6193 AN: 26126

East Asian (EAS) AF: 0.359 AC: 14249 AN: 39688

South Asian (SAS) AF: 0.275 AC: 23678 AN: 86132

European-Finnish (FIN) AF: 0.269 AC: 14383 AN: 53400

Middle Eastern (MID) AF: 0.238 AC: 986 AN: 4146

European-Non Finnish (NFE) AF: 0.226 AC: 251361 AN: 1110990

Other (OTH) AF: 0.229 AC: 13786 AN: 60174

GnomAD4 genome AF: 0.202 AC: 30667 AN: 152026 Hom.: 3678 Cov.: 32 AF XY: 0.205 AC XY: 15224 AN XY: 74316

African (AFR) AF: 0.0731 AC: 3030 AN: 41462

American (AMR) AF: 0.301 AC: 4603 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3468

East Asian (EAS) AF: 0.328 AC: 1688 AN: 5148

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4824

European-Finnish (FIN) AF: 0.276 AC: 2921 AN: 10590

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.229 AC: 15549 AN: 67932

Other (OTH) AF: 0.220 AC: 466 AN: 2116

Alfa AF: 0.211 Hom.: 667

Bravo AF: 0.200

Asia WGS AF: 0.247 AC: 859 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 31 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.69
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4979386; hg19: chr9-117186592; COSMIC: COSV54331182;