rs187221008

Positions:

• chr9-114408023-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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:4 B:5
• Conservation: PhyloP100: 0.541

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]

ACMG classification

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	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	c.1627-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015404.4	ENSP00000354623	P1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152224 Hom.: 2 Cov.: 33

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.: 3 AF XY: 0.00153 AC XY: 179 AN XY: 117210

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.: 4 Cov.: 31 AF XY: 0.00217 AC XY: 1554 AN XY: 716214

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.: 2 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74490

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.: 0

Bravo AF: 0.00169

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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

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. -

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	17
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

Other links and lift over

dbSNP: rs187221008; hg19: chr9-117170303;