9-114404267-A-G

Variant names:

• chr9-114404267-A-G
• rs766835
• NM_015404.4:c.2237-190T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.2237-190T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 151,946 control chromosomes in the GnomAD database, including 3,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.20 (3577 hom., cov: 32)
• Consequence: WHRN NM_015404.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.886
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-114404267-A-G is Benign according to our data. Variant chr9-114404267-A-G is described in ClinVar as Benign. ClinVar VariationId is 678811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.2237-190T>C		intron	N/A	NP_056219.3
	WHRN	NM_001173425.2		c.2237-193T>C		intron	N/A	NP_001166896.1
	WHRN	NM_001346890.1		c.1184-190T>C		intron	N/A	NP_001333819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.2237-190T>C		intron	N/A	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.1088-190T>C		intron	N/A	ENSP00000265134.6
	WHRN	ENST00000674036.9		c.2027-190T>C		intron	N/A	ENSP00000501297.5

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30487 AN: 151824 Hom.: 3571 Cov.: 32

Gnomad AFR AF: 0.0758

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.219

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

GnomAD4 genome AF: 0.201 AC: 30508 AN: 151946 Hom.: 3577 Cov.: 32 AF XY: 0.205 AC XY: 15189 AN XY: 74252

African (AFR) AF: 0.0757 AC: 3136 AN: 41454

American (AMR) AF: 0.279 AC: 4259 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 866 AN: 3472

East Asian (EAS) AF: 0.331 AC: 1700 AN: 5138

South Asian (SAS) AF: 0.264 AC: 1268 AN: 4810

European-Finnish (FIN) AF: 0.289 AC: 3051 AN: 10556

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15523 AN: 67906

Other (OTH) AF: 0.217 AC: 459 AN: 2114

Alfa AF: 0.107 Hom.: 172

Bravo AF: 0.196

Asia WGS AF: 0.245 AC: 849 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.89
DANN	Benign	0.72
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs766835; hg19: chr9-117166547;