9-114424183-T-C

Variant names:

• chr9-114424183-T-C
• rs4979385
• NM_015404.4:c.1416+151A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015404.4(WHRN):​c.1416+151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 873,868 control chromosomes in the GnomAD database, including 73,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.44 (15432 hom., cov: 32)
  • Exomes 𝑓: 0.39 (57926 hom.)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.602
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-114424183-T-C is Benign according to our data. Variant chr9-114424183-T-C is described in ClinVar as Benign. ClinVar VariationId is 678808.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.1416+151A>G		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+151A>G		intron_variant	Intron 6 of 11	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67127 AN: 151968 Hom.: 15395 Cov.: 32

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.419

GnomAD4 exome AF: 0.392 AC: 283275 AN: 721782 Hom.: 57926 AF XY: 0.388 AC XY: 146374 AN XY: 376994

African (AFR) AF: 0.563 AC: 10858 AN: 19296

American (AMR) AF: 0.592 AC: 20200 AN: 34136

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 5822 AN: 18648

East Asian (EAS) AF: 0.399 AC: 13972 AN: 35016

South Asian (SAS) AF: 0.391 AC: 24968 AN: 63856

European-Finnish (FIN) AF: 0.408 AC: 18567 AN: 45500

Middle Eastern (MID) AF: 0.338 AC: 863 AN: 2552

European-Non Finnish (NFE) AF: 0.372 AC: 174137 AN: 467596

Other (OTH) AF: 0.395 AC: 13888 AN: 35182

GnomAD4 genome AF: 0.442 AC: 67224 AN: 152086 Hom.: 15432 Cov.: 32 AF XY: 0.441 AC XY: 32769 AN XY: 74328

African (AFR) AF: 0.556 AC: 23067 AN: 41490

American (AMR) AF: 0.508 AC: 7773 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1168 AN: 3468

East Asian (EAS) AF: 0.371 AC: 1917 AN: 5172

South Asian (SAS) AF: 0.396 AC: 1909 AN: 4818

European-Finnish (FIN) AF: 0.409 AC: 4324 AN: 10566

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25815 AN: 67970

Other (OTH) AF: 0.416 AC: 877 AN: 2110

Alfa AF: 0.178 Hom.: 309

Bravo AF: 0.459

Asia WGS AF: 0.369 AC: 1283 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.94
DANN	Benign	0.36
PhyloP100		-0.60
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: rs4979385; hg19: chr9-117186463; COSMIC: COSV54335029;