NM_015404.4:c.1318G>A

Variant names:

• chr9-114424432-C-T
• rs4978584
• NM_015404.4:c.1318G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.1318G>A​(p.Ala440Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,613,244 control chromosomes in the GnomAD database, including 46,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A440A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3635 hom., cov: 32)
  • Exomes 𝑓: 0.23 (42613 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.58
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030617118).
• BP6: Variant 9-114424432-C-T is Benign according to our data. Variant chr9-114424432-C-T is described in ClinVar as Benign. ClinVar VariationId is 45647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 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.1318G>A	p.Ala440Thr	missense	Exon 6 of 12	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.1318G>A	p.Ala440Thr	missense	Exon 6 of 12	NP_001166896.1
	WHRN	NM_001346890.1		c.265G>A	p.Ala89Thr	missense	Exon 2 of 8	NP_001333819.1	Q9P202-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1318G>A	p.Ala440Thr	missense	Exon 6 of 12	ENSP00000354623.3	Q9P202-1
	WHRN	ENST00000265134.10	TSL:1	c.169G>A	p.Ala57Thr	missense	Exon 6 of 12	ENSP00000265134.6	Q9P202-3
	WHRN	ENST00000866780.1		c.1318G>A	p.Ala440Thr	missense	Exon 6 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30683 AN: 152040 Hom.: 3627 Cov.: 32

Gnomad AFR AF: 0.0790

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.221

GnomAD2 exomes AF: 0.262 AC: 65724 AN: 251210 AF XY: 0.257

Gnomad AFR exome AF: 0.0744

Gnomad AMR exome AF: 0.425

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.328

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.235 AC: 343333 AN: 1461086 Hom.: 42613 Cov.: 53 AF XY: 0.236 AC XY: 171366 AN XY: 726842

African (AFR) AF: 0.0696 AC: 2328 AN: 33462

American (AMR) AF: 0.411 AC: 18357 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6053 AN: 26134

East Asian (EAS) AF: 0.358 AC: 14212 AN: 39698

South Asian (SAS) AF: 0.274 AC: 23590 AN: 86220

European-Finnish (FIN) AF: 0.268 AC: 14331 AN: 53412

Middle Eastern (MID) AF: 0.219 AC: 1147 AN: 5226

European-Non Finnish (NFE) AF: 0.225 AC: 249636 AN: 1111886

Other (OTH) AF: 0.227 AC: 13679 AN: 60332

GnomAD4 genome AF: 0.202 AC: 30714 AN: 152158 Hom.: 3635 Cov.: 32 AF XY: 0.205 AC XY: 15251 AN XY: 74382

African (AFR) AF: 0.0789 AC: 3278 AN: 41544

American (AMR) AF: 0.299 AC: 4567 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 843 AN: 3470

East Asian (EAS) AF: 0.326 AC: 1682 AN: 5156

South Asian (SAS) AF: 0.270 AC: 1301 AN: 4818

European-Finnish (FIN) AF: 0.274 AC: 2908 AN: 10594

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15434 AN: 67980

Other (OTH) AF: 0.218 AC: 460 AN: 2108

Alfa AF: 0.219 Hom.: 13104

Bravo AF: 0.201

TwinsUK AF: 0.226 AC: 839

ALSPAC AF: 0.248 AC: 955

ESP6500AA AF: 0.0831 AC: 366

ESP6500EA AF: 0.230 AC: 1975

ExAC AF: 0.252 AC: 30629

Asia WGS AF: 0.245 AC: 849 AN: 3478

EpiCase AF: 0.224

EpiControl AF: 0.221

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.023
Sift	Benign	0.097	T
Sift4G	Benign	0.31	T
Polyphen		0.0060	B
Vest4		0.12
MPC		0.12
ClinPred		0.0057	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.022
gMVP		0.20
Mutation Taster		=96/4	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: rs4978584; hg19: chr9-117186712; COSMIC: COSV54326804;