9-114467120-T-G

Variant names:

• chr9-114467120-T-G
• rs1535971
• NM_015404.4:c.838-728A>C

Variant summary

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

The NM_015404.4(WHRN):​c.838-728A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 149,982 control chromosomes in the GnomAD database, including 34,514 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 0.66 (34514 hom., cov: 28)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.66
• Publications: 2 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4	c.838-728A>C		intron_variant	Intron 2 of 11	ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4	c.838-728A>C		intron_variant	Intron 2 of 11	1	NM_015404.4	ENSP00000354623.3

Frequencies

GnomAD3 genomes AF: 0.665 AC: 99608 AN: 149858 Hom.: 34487 Cov.: 28

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.682

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

GnomAD4 genome AF: 0.665 AC: 99677 AN: 149982 Hom.: 34514 Cov.: 28 AF XY: 0.666 AC XY: 48819 AN XY: 73278

African (AFR) AF: 0.442 AC: 17862 AN: 40376

American (AMR) AF: 0.767 AC: 11647 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2345 AN: 3454

East Asian (EAS) AF: 0.929 AC: 4723 AN: 5082

South Asian (SAS) AF: 0.863 AC: 4119 AN: 4774

European-Finnish (FIN) AF: 0.683 AC: 7115 AN: 10418

Middle Eastern (MID) AF: 0.651 AC: 185 AN: 284

European-Non Finnish (NFE) AF: 0.734 AC: 49511 AN: 67440

Other (OTH) AF: 0.685 AC: 1425 AN: 2080

Alfa AF: 0.714 Hom.: 69563

Bravo AF: 0.659

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.6
DANN	Benign	0.37
PhyloP100		-2.7
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: rs1535971; hg19: chr9-117229400; COSMIC: COSV54328982;