9-114460395-G-A

Variant names:

• chr9-114460395-G-A
• rs4979402
• NM_015404.4:c.963+5872C>T

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+5872C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 152,208 control chromosomes in the GnomAD database, including 42,470 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 (42470 hom., cov: 33)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.233
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.963+5872C>T		intron	N/A	NP_056219.3
	WHRN	NM_001173425.2		c.963+5872C>T		intron	N/A	NP_001166896.1
	WHRN	NM_001083885.3		c.-187+5872C>T		intron	N/A	NP_001077354.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.963+5872C>T		intron	N/A	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.-187+5872C>T		intron	N/A	ENSP00000265134.6
	WHRN	ENST00000674036.9		c.963+5872C>T		intron	N/A	ENSP00000501297.5

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113344 AN: 152088 Hom.: 42431 Cov.: 33

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.794

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.737

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

GnomAD4 genome AF: 0.745 AC: 113436 AN: 152208 Hom.: 42470 Cov.: 33 AF XY: 0.745 AC XY: 55436 AN XY: 74406

African (AFR) AF: 0.708 AC: 29406 AN: 41506

American (AMR) AF: 0.795 AC: 12162 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2424 AN: 3470

East Asian (EAS) AF: 0.966 AC: 5009 AN: 5186

South Asian (SAS) AF: 0.831 AC: 4012 AN: 4830

European-Finnish (FIN) AF: 0.688 AC: 7288 AN: 10590

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50618 AN: 68004

Other (OTH) AF: 0.741 AC: 1567 AN: 2116

Alfa AF: 0.745 Hom.: 70830

Bravo AF: 0.753

Asia WGS AF: 0.868 AC: 3016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.64
PhyloP100		0.23
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: rs4979402; hg19: chr9-117222675;