chr9-114408023-A-T

Position:

chr9-114408023-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015404.4(WHRN):c.1627-5T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,595,730 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 4 hom. )

Consequence

WHRN
NM_015404.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.8084

Clinical Significance

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

Conservation

PhyloP100: 0.541

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 9-114408023-A-T is Benign according to our data. Variant chr9-114408023-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163048.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=3}. Variant chr9-114408023-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (266/152342) while in subpopulation NFE AF= 0.00276 (188/68036). AF 95% confidence interval is 0.00244. There are 2 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.1627-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000362057.4	NP_056219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WHRN	ENST00000362057.4 linkuse as main transcript	c.1627-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015404.4	ENSP00000354623	P1	Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

266

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00276

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00155

AC:

337

AN:

218004

Hom.:

AF XY:

0.00153

AC XY:

179

AN XY:

117210

show subpopulations

Gnomad AFR exome

AF:

0.000675

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000481

Gnomad FIN exome

AF:

0.000638

Gnomad NFE exome

AF:

0.00297

Gnomad OTH exome

AF:

0.00235

GnomAD4 exome

AF:

0.00224

AC:

3238

AN:

1443388

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1554

AN XY:

716214

show subpopulations

Gnomad4 AFR exome

AF:

0.000363

Gnomad4 AMR exome

AF:

0.000187

Gnomad4 ASJ exome

AF:

0.0000779

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000335

Gnomad4 FIN exome

AF:

0.000996

Gnomad4 NFE exome

AF:

0.00277

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00175

AC:

266

AN:

152342

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00276

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00185

Hom.:

Bravo

AF:

0.00169

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2020	This variant is associated with the following publications: (PMID: 27208204, 23591405) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	WHRN: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Autosomal recessive nonsyndromic hearing loss 31

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 2D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Retinal dystrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 26, 2013

1627-5T>A in Intron 7 of DFNB31: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (26/8600) of European America ns by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs187221008), and computational tools do not suggest an impact to splicing. -

WHRN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.81

dbscSNV1_RF

Benign

0.56

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over