9-114482852-G-A

Variant names:

• chr9-114482852-G-A
• rs16929545
• NM_015404.4:c.619-4081C>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.619-4081C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,126 control chromosomes in the GnomAD database, including 1,638 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 0.13 (1638 hom., cov: 31)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.988
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 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.619-4081C>T		intron	N/A	NP_056219.3
	WHRN	NM_001173425.2		c.619-4081C>T		intron	N/A	NP_001166896.1
	WHRN	NM_001083885.3		c.-531-4081C>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.619-4081C>T		intron	N/A	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.-531-4081C>T		intron	N/A	ENSP00000265134.6
	WHRN	ENST00000674036.9		c.619-4081C>T		intron	N/A	ENSP00000501297.5

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19851 AN: 152006 Hom.: 1636 Cov.: 31

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.139

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

GnomAD4 genome AF: 0.130 AC: 19845 AN: 152126 Hom.: 1638 Cov.: 31 AF XY: 0.128 AC XY: 9542 AN XY: 74358

African (AFR) AF: 0.0355 AC: 1475 AN: 41514

American (AMR) AF: 0.121 AC: 1847 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3470

East Asian (EAS) AF: 0.143 AC: 739 AN: 5158

South Asian (SAS) AF: 0.211 AC: 1010 AN: 4796

European-Finnish (FIN) AF: 0.102 AC: 1074 AN: 10580

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12673 AN: 68000

Other (OTH) AF: 0.138 AC: 291 AN: 2112

Alfa AF: 0.167 Hom.: 2941

Bravo AF: 0.127

Asia WGS AF: 0.139 AC: 483 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.18
DANN	Benign	0.66
PhyloP100		-0.99
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: rs16929545; hg19: chr9-117245132;