12-105107849-G-A

Position:

chr12-105107849-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The ENST00000332180.10(WASHC4):c.49G>A(p.Asp17Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00026 in 1,550,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D17E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

WASHC4
ENST00000332180.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.79

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008968204).

BP6

Variant 12-105107849-G-A is Benign according to our data. Variant chr12-105107849-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 742318.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00145 (221/152304) while in subpopulation AFR AF= 0.00498 (207/41566). AF 95% confidence interval is 0.00442. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC4	NM_015275.3 linkuse as main transcript	c.49G>A	p.Asp17Asn	missense_variant	1/33	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.49G>A	p.Asp17Asn	missense_variant	1/33	1	NM_015275.3	ENSP00000328062	A1	Q2M389-1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000719

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000255

AC:

AN:

153222

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

81254

show subpopulations

Gnomad AFR exome

AF:

0.00356

Gnomad AMR exome

AF:

0.000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000169

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.000130

AC:

182

AN:

1398166

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

689728

show subpopulations

Gnomad4 AFR exome

AF:

0.00450

Gnomad4 AMR exome

AF:

0.000308

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000464

Gnomad4 OTH exome

AF:

0.000345

GnomAD4 genome

AF:

0.00145

AC:

221

AN:

152304

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00498

Gnomad4 AMR

AF:

0.000718

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000553

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.00102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000155

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 43

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 19, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

WASHC4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 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

Uncertain

0.54

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.0090

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.14

Sift

Benign

0.14

T;.

Sift4G

Benign

0.12

T;T

Polyphen

0.73

P;.

Vest4

0.43

MVP

0.58

MPC

0.54

ClinPred

0.087

GERP RS

4.1

Varity_R

0.50

gMVP

0.57

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