Genetic Variant NM_015404.4:c.1149C>T (chr9-114426228-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_015404.4(WHRN):c.1149C>T(p.Thr383Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,612,412 control chromosomes in the GnomAD database, including 1 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 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

WHRN
NM_015404.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.664

Publications

1 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 9-114426228-G-A is Benign according to our data. Variant chr9-114426228-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45642.

BP7

Synonymous conserved (PhyloP=0.664 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000912 (139/152330) while in subpopulation NFE AF = 0.00162 (110/68034). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.1149C>T	p.Thr383Thr	synonymous	Exon 4 of 12	NP_056219.3	Q9P202-1
WHRN	NM_001173425.2		c.1149C>T	p.Thr383Thr	synonymous	Exon 4 of 12	NP_001166896.1
WHRN	NM_001083885.3		c.-1C>T		5_prime_UTR	Exon 4 of 12	NP_001077354.2	Q9P202-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1149C>T	p.Thr383Thr	synonymous	Exon 4 of 12	ENSP00000354623.3	Q9P202-1
WHRN	ENST00000265134.10	TSL:1	c.-1C>T		5_prime_UTR	Exon 4 of 12	ENSP00000265134.6	Q9P202-3
WHRN	ENST00000866780.1		c.1149C>T	p.Thr383Thr	synonymous	Exon 4 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes

AF:

0.000913

AC:

139

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000888

AC:

223

AN:

251194

AF XY:

0.000928

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00137

AC:

2001

AN:

1460082

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

977

AN XY:

726354

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33420

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4338

European-Non Finnish (NFE)

AF:

0.00166

AC:

1850

AN:

1111998

Other (OTH)

AF:

0.00129

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

129

258

387

516

645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.000912

AC:

139

AN:

152330

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41574

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00162

AC:

110

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.00130

Hom.:

Bravo

AF:

0.000861

EpiCase

AF:

0.00120

EpiControl

AF:

0.00172

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 (2)

Autosomal recessive nonsyndromic hearing loss 31 (1)

Usher syndrome type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.46

(source)

DANN

Benign

0.69

PhyloP100

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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