NM_015404.4:c.1678G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_015404.4(WHRN):c.1678G>A(p.Ala560Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,603,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -1.01

Publications

5 publications found

Variant links:

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

WHRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013188064).

BP6

Variant 9-114407967-C-T is Benign according to our data. Variant chr9-114407967-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163047.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000361 (55/152302) while in subpopulation NFE AF = 0.000426 (29/68026). AF 95% confidence interval is 0.000304. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WHRN	NM_015404.4	MANE Select	c.1678G>A	p.Ala560Thr	missense	Exon 8 of 12	NP_056219.3	Q9P202-1
WHRN	NM_001173425.2		c.1678G>A	p.Ala560Thr	missense	Exon 8 of 12	NP_001166896.1
WHRN	NM_001346890.1		c.625G>A	p.Ala209Thr	missense	Exon 4 of 8	NP_001333819.1	Q9P202-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1678G>A	p.Ala560Thr	missense	Exon 8 of 12	ENSP00000354623.3	Q9P202-1
WHRN	ENST00000265134.10	TSL:1	c.529G>A	p.Ala177Thr	missense	Exon 8 of 12	ENSP00000265134.6	Q9P202-3
WHRN	ENST00000866780.1		c.1678G>A	p.Ala560Thr	missense	Exon 8 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000391

AC:

AN:

232622

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.0000695

Gnomad AMR exome

AF:

0.0000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.000549

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000377

AC:

547

AN:

1451016

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

275

AN XY:

720686

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33244

American (AMR)

AF:

0.0000457

AC:

AN:

43716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25878

East Asian (EAS)

AF:

0.00

AC:

AN:

39378

South Asian (SAS)

AF:

0.0000237

AC:

AN:

84288

European-Finnish (FIN)

AF:

0.00289

AC:

152

AN:

52596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000321

AC:

355

AN:

1106220

Other (OTH)

AF:

0.000534

AC:

AN:

59950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000361

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41546

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000374

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000404

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

WHRN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0060

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.057

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.61

M_CAP

Benign

0.0027

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.13

PhyloP100

-1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.15

REVEL

Benign

0.026

Sift

Benign

0.61

Sift4G

Benign

0.93

Polyphen

0.054

Vest4

0.023

MVP

0.014

MPC

0.12

ClinPred

0.0072

GERP RS

-6.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.22

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over