rs45527543

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015404.4(WHRN):c.33C>G(p.Ser11Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00155 in 1,495,928 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

WHRN
NM_015404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4O:1

Conservation

PhyloP100: 3.63

Publications

2 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064022243).

BP6

Variant 9-114504769-G-C is Benign according to our data. Variant chr9-114504769-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45677.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00129 (197/152296) while in subpopulation NFE AF = 0.00199 (135/68006). AF 95% confidence interval is 0.00171. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

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.33C>G	p.Ser11Arg	missense	Exon 1 of 12	NP_056219.3	Q9P202-1
	WHRN	NM_001173425.2		c.33C>G	p.Ser11Arg	missense	Exon 1 of 12	NP_001166896.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WHRN	ENST00000362057.4	TSL:1 MANE Select	c.33C>G	p.Ser11Arg	missense	Exon 1 of 12	ENSP00000354623.3	Q9P202-1
WHRN	ENST00000866780.1		c.33C>G	p.Ser11Arg	missense	Exon 1 of 12	ENSP00000536839.1
WHRN	ENST00000929560.1		c.33C>G	p.Ser11Arg	missense	Exon 1 of 11	ENSP00000599619.1

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

197

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00111

AC:

101

AN:

90864

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00371

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000395

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.000356

GnomAD4 exome

AF:

0.00158

AC:

2123

AN:

1343632

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

994

AN XY:

662574

show subpopulations

African (AFR)

AF:

0.000291

AC:

AN:

27460

American (AMR)

AF:

0.00144

AC:

AN:

28418

Ashkenazi Jewish (ASJ)

AF:

0.00524

AC:

119

AN:

22706

East Asian (EAS)

AF:

0.00

AC:

AN:

32608

South Asian (SAS)

AF:

0.00

AC:

AN:

73218

European-Finnish (FIN)

AF:

0.000119

AC:

AN:

33496

Middle Eastern (MID)

AF:

0.000502

AC:

AN:

3988

European-Non Finnish (NFE)

AF:

0.00174

AC:

1858

AN:

1065816

Other (OTH)

AF:

0.00163

AC:

AN:

55922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

138

276

414

552

690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00129

AC:

197

AN:

152296

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41572

American (AMR)

AF:

0.00170

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00199

AC:

135

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00149

Hom.:

Bravo

AF:

0.00158

ExAC

AF:

0.000415

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal recessive nonsyndromic hearing loss 31 (1)

not specified (1)

Retinitis pigmentosa-deafness syndrome (1)

Usher syndrome type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

Eigen

Benign

-0.056

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

3.6

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.67

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.030

Polyphen

0.0

Vest4

0.22

MutPred

0.20

Loss of phosphorylation at S11 (P = 0.0172)

MVP

0.30

MPC

1.7

ClinPred

0.10

GERP RS

5.0

Varity_R

0.25

gMVP

0.49

Mutation Taster

=20/80

disease causing

(source)

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

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