9-114404031-G-A

Variant names:

• chr9-114404031-G-A
• rs34963246
• NM_015404.4:c.2283C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015404.4(WHRN):​c.2283C>T​(p.Ser761Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,613,262 control chromosomes in the GnomAD database, including 8,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1261 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6784 hom.)
• Consequence: WHRN NM_015404.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.750
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 9-114404031-G-A is Benign according to our data. Variant chr9-114404031-G-A is described in ClinVar as Benign. ClinVar VariationId is 45669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 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.2283C>T	p.Ser761Ser	synonymous	Exon 10 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.2280C>T	p.Ser760Ser	synonymous	Exon 10 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.1230C>T	p.Ser410Ser	synonymous	Exon 6 of 8	NP_001333819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.2283C>T	p.Ser761Ser	synonymous	Exon 10 of 12	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.1134C>T	p.Ser378Ser	synonymous	Exon 10 of 12	ENSP00000265134.6
	WHRN	ENST00000674036.9		c.2073C>T	p.Ser691Ser	synonymous	Exon 9 of 11	ENSP00000501297.5

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17718 AN: 152186 Hom.: 1256 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0907

Gnomad OTH AF: 0.0889

GnomAD2 exomes AF: 0.0914 AC: 22906 AN: 250592 AF XY: 0.0843

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0928

Gnomad OTH exome AF: 0.0813

GnomAD4 exome AF: 0.0901 AC: 131660 AN: 1460958 Hom.: 6784 Cov.: 37 AF XY: 0.0864 AC XY: 62761 AN XY: 726752

African (AFR) AF: 0.202 AC: 6749 AN: 33474

American (AMR) AF: 0.148 AC: 6599 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 937 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0254 AC: 2194 AN: 86256

European-Finnish (FIN) AF: 0.118 AC: 6212 AN: 52570

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5768

European-Non Finnish (NFE) AF: 0.0932 AC: 103675 AN: 1111950

Other (OTH) AF: 0.0851 AC: 5141 AN: 60388

GnomAD4 genome AF: 0.116 AC: 17738 AN: 152304 Hom.: 1261 Cov.: 33 AF XY: 0.115 AC XY: 8551 AN XY: 74480

African (AFR) AF: 0.192 AC: 7974 AN: 41570

American (AMR) AF: 0.130 AC: 1983 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3468

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4822

European-Finnish (FIN) AF: 0.107 AC: 1139 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0908 AC: 6174 AN: 68028

Other (OTH) AF: 0.0880 AC: 186 AN: 2114

Alfa AF: 0.0983 Hom.: 422

Bravo AF: 0.123

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0803

EpiControl AF: 0.0805

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	3.7
DANN	Benign	0.73
PhyloP100		-0.75
Mutation Taster		=88/12	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: rs34963246; hg19: chr9-117166311; COSMIC: COSV54335995;