9-114457608-T-C

Variant names:

• chr9-114457608-T-C
• rs4979397
• NM_015404.4:c.963+8659A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015404.4(WHRN):​c.963+8659A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 151,862 control chromosomes in the GnomAD database, including 42,459 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (42459 hom., cov: 30)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.963+8659A>G		intron_variant	Intron 3 of 11	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.963+8659A>G		intron_variant	Intron 3 of 11	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113202 AN: 151744 Hom.: 42420 Cov.: 30

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.650

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.740

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.746 AC: 113293 AN: 151862 Hom.: 42459 Cov.: 30 AF XY: 0.746 AC XY: 55326 AN XY: 74200

African (AFR) AF: 0.709 AC: 29348 AN: 41402

American (AMR) AF: 0.796 AC: 12157 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2419 AN: 3462

East Asian (EAS) AF: 0.965 AC: 4962 AN: 5142

South Asian (SAS) AF: 0.832 AC: 4000 AN: 4808

European-Finnish (FIN) AF: 0.688 AC: 7240 AN: 10520

Middle Eastern (MID) AF: 0.668 AC: 195 AN: 292

European-Non Finnish (NFE) AF: 0.746 AC: 50653 AN: 67944

Other (OTH) AF: 0.742 AC: 1565 AN: 2108

Alfa AF: 0.746 Hom.: 70444

Bravo AF: 0.753

Asia WGS AF: 0.868 AC: 3018 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.4
DANN	Benign	0.52
PhyloP100		-1.5
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: rs4979397; hg19: chr9-117219888;