Genetic Variant WHRN:c.838-728A>T (chr9-114467120-T-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_015404.4(WHRN):c.838-728A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 150,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 28)

Consequence

WHRN
NM_015404.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.66

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 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

WHRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00115 (173/150058) while in subpopulation NFE AF = 0.0019 (128/67460). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WHRN	NM_015404.4 link	c.838-728A>T		intron_variant	Intron 2 of 11	ENST00000362057.4	NP_056219.3	Q9P202-1B9EGE6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4 link	c.838-728A>T		intron_variant	Intron 2 of 11	1	NM_015404.4	ENSP00000354623.3		Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

173

AN:

149934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000521

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000330

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00188

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00291

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.00115

AC:

173

AN:

150058

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

73320

show subpopulations

African (AFR)

AF:

0.000520

AC:

AN:

40408

American (AMR)

AF:

0.000329

AC:

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00189

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10434

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00190

AC:

128

AN:

67460

Other (OTH)

AF:

0.00288

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00000746

Hom.:

69563

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.5

(source)

DANN

Benign

0.35

PhyloP100

-2.7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over