Variant chr9-114426302-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008066028).

BP6

Variant 9-114426302-C-T is Benign according to our data. Variant chr9-114426302-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288922.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000551 (84/152348) while in subpopulation AFR AF= 0.00192 (80/41578). AF 95% confidence interval is 0.00158. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4 linkuse as main transcript	c.1075G>A	p.Val359Ile	missense_variant	4/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4 linkuse as main transcript	c.1075G>A	p.Val359Ile	missense_variant	4/12	1	NM_015404.4	P1	Q9P202-1

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

83

AN:

152230

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000283

AC:

71

AN:

251160

Hom.:

1

AF XY:

0.000339

AC XY:

46

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

186

AN:

1461432

Hom.:

1

Cov.:

30

AF XY:

0.000160

AC XY:

116

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000551

AC:

84

AN:

152348

Hom.:

0

Cov.:

33

AF XY:

0.000564

AC XY:

42

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

0

Bravo

AF:

0.000616

ESP6500AA

AF:

0.000908

AC:

4

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.000371

AC:

45

Asia WGS

AF:

0.00173

AC:

6

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2016	p.Val359Ile in exon 4 of DFNB31: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, three mammals (cow, hedgehog, and platypus) have an isoleucine (Ile) at th is position despite high nearby amino acid conservation. In addition, computatio nal prediction tools do not suggest a high likelihood of impact to the protein. This variant has been identified in 0.2% (21/10300) of African chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14 7500559). -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	- -

Autosomal recessive nonsyndromic hearing loss 31

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 2D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

WHRN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2022

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.53

T

BayesDel_noAF

Benign

-0.55

CADD

Benign

19

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.81

D

LIST_S2

Benign

0.82

T

M_CAP

Benign

0.0052

T

MetaRNN

Benign

0.0081

T

MetaSVM

Benign

-1.1

T

MutationAssessor

Benign

0.30

N

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

T

PROVEAN

Benign

-0.70

N

REVEL

Benign

0.0070

Sift

Benign

0.14

T

Sift4G

Benign

0.21

T

Polyphen

0.0010

B

Vest4

0.10

MVP

0.13

MPC

0.098

ClinPred

0.014

T

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.19

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

LitVar

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

chr9-114426302-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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