rs35267264

Positions:

chr12-105126095-G-A

Variant summary

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

The ENST00000332180.10(WASHC4):c.878G>A(p.Arg293Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,612,812 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 10 hom. )

Consequence

WASHC4
ENST00000332180.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 8.15

Variant links:

Genes affected

WASHC4 (HGNC:29174): (WASH complex subunit 4) This gene encodes a component of the WASH complex, which functions in the intracellular transport of endosomes. Mutations in this gene have been detected in individuals with autosomal recessive cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

WASHC4 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 (MetaRNN=0.055656135).

BP6

Variant 12-105126095-G-A is Benign according to our data. Variant chr12-105126095-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225042.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00144 (219/152110) while in subpopulation NFE AF= 0.00264 (179/67914). AF 95% confidence interval is 0.00232. There are 0 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC4	NM_015275.3 linkuse as main transcript	c.878G>A	p.Arg293Gln	missense_variant	11/33	ENST00000332180.10	NP_056090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC4	ENST00000332180.10 linkuse as main transcript	c.878G>A	p.Arg293Gln	missense_variant	11/33	1	NM_015275.3	ENSP00000328062	A1	Q2M389-1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00264

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.00162

AC:

403

AN:

248514

Hom.:

AF XY:

0.00165

AC XY:

223

AN XY:

134854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00265

Gnomad OTH exome

AF:

0.00331

GnomAD4 exome

AF:

0.00175

AC:

2549

AN:

1460702

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1282

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00206

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00144

AC:

219

AN:

152110

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00264

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.00194

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00174

AC:

210

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00338

EpiControl

AF:

0.00386

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	WASHC4: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 21, 2016	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2012

N/AN/ABased on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.12% (11/9498 total alleles studied). The A-allele was observed in 0.17% of European American (11/6556 alleles), was not observed among 2942 African American alleles studied, and has not been observed in the homozygous state among 4749 individuals studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 2/2188 (0.09%) and the highest frequency was in the British (0.56% 1/178 alleles). This amino acid position is completely conserved in available vertebrate species.This alteration is predicted to be possibly damaging with a score of 0.770 (sensitivity: 0.76; specificity: 0.86)This alteration is predicted to be tolerated with a score of 0.340 (conservation: 1.75) -

WASHC4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

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

0.21

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.031

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.88

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.25

Sift

Benign

0.066

T;.

Sift4G

Benign

0.062

T;T

Polyphen

0.99

D;.

Vest4

0.86

MVP

0.65

MPC

0.72

ClinPred

0.049

GERP RS

5.6

Varity_R

0.26

gMVP

0.61

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.

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