NM_015404.4:c.117G>A

Variant names:

• chr9-114504685-C-T
• rs2297815
• NM_015404.4:c.117G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.117G>A​(p.Val39Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,592,880 control chromosomes in the GnomAD database, including 100,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8605 hom., cov: 34)
  • Exomes 𝑓: 0.35 (92071 hom.)
• Consequence: WHRN NM_015404.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.584
• Publications: 20 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, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• autosomal recessive nonsyndromic hearing loss 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-114504685-C-T is Benign according to our data. Variant chr9-114504685-C-T is described in ClinVar as Benign. ClinVar VariationId is 45644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.117G>A	p.Val39Val	synonymous	Exon 1 of 12	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.117G>A	p.Val39Val	synonymous	Exon 1 of 12	NP_001166896.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.117G>A	p.Val39Val	synonymous	Exon 1 of 12	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000866780.1		c.117G>A	p.Val39Val	synonymous	Exon 1 of 12	ENSP00000536839.1
	WHRN	ENST00000929560.1		c.117G>A	p.Val39Val	synonymous	Exon 1 of 11	ENSP00000599619.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49598 AN: 152038 Hom.: 8609 Cov.: 34

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.326 AC: 69865 AN: 214404 AF XY: 0.325

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.353 AC: 508433 AN: 1440726 Hom.: 92071 Cov.: 40 AF XY: 0.350 AC XY: 250231 AN XY: 715960

African (AFR) AF: 0.227 AC: 7493 AN: 32980

American (AMR) AF: 0.326 AC: 14211 AN: 43582

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 8967 AN: 25366

East Asian (EAS) AF: 0.172 AC: 6757 AN: 39248

South Asian (SAS) AF: 0.226 AC: 19117 AN: 84554

European-Finnish (FIN) AF: 0.487 AC: 21559 AN: 44252

Middle Eastern (MID) AF: 0.305 AC: 1591 AN: 5220

European-Non Finnish (NFE) AF: 0.370 AC: 409326 AN: 1105912

Other (OTH) AF: 0.326 AC: 19412 AN: 59612

GnomAD4 genome AF: 0.326 AC: 49587 AN: 152154 Hom.: 8605 Cov.: 34 AF XY: 0.329 AC XY: 24498 AN XY: 74374

African (AFR) AF: 0.236 AC: 9795 AN: 41540

American (AMR) AF: 0.336 AC: 5139 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1193 AN: 3470

East Asian (EAS) AF: 0.139 AC: 717 AN: 5164

South Asian (SAS) AF: 0.220 AC: 1062 AN: 4834

European-Finnish (FIN) AF: 0.507 AC: 5363 AN: 10578

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.372 AC: 25248 AN: 67956

Other (OTH) AF: 0.321 AC: 678 AN: 2114

Alfa AF: 0.339 Hom.: 3641

Bravo AF: 0.308

Asia WGS AF: 0.204 AC: 713 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 31 (2)
-	-	2	not specified (2)
-	-	1	Usher syndrome type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.58
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: rs2297815; hg19: chr9-117266965; COSMIC: COSV54328205; COSMIC: COSV54328205;