chr12-105144435-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_015275.3(WASHC4):c.2159A>G(p.Asn720Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,612,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

WASHC4
NM_015275.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4B:1

Conservation

PhyloP100: 6.17

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015016794).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000305 (46/151036) while in subpopulation EAS AF= 0.00155 (8/5160). AF 95% confidence interval is 0.000771. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC4	NM_015275.3 link	c.2159A>G	p.Asn720Ser	missense_variant	Exon 21 of 33	ENST00000332180.10	NP_056090.1	Q2M389-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC4	ENST00000332180.10 link	c.2159A>G	p.Asn720Ser	missense_variant	Exon 21 of 33	1	NM_015275.3	ENSP00000328062.6		Q2M389-1

Frequencies

GnomAD3 genomes

AF:

0.000285

AC:

AN:

150946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000656

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000740

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000325

AC:

AN:

249314

Hom.:

AF XY:

0.000333

AC XY:

AN XY:

135282

show subpopulations

Gnomad AFR exome

AF:

0.000775

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00195

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000233

AC:

341

AN:

1461510

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

169

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00366

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000305

AC:

AN:

151036

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

AN XY:

73792

show subpopulations

Gnomad4 AFR

AF:

0.000727

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000740

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000758

Hom.:

Bravo

AF:

0.000272

ExAC

AF:

0.000364

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2024	The c.2159A>G (p.N720S) alteration is located in exon 21 (coding exon 21) of the KIAA1033 gene. This alteration results from a A to G substitution at nucleotide position 2159, causing the asparagine (N) at amino acid position 720 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 21, 2020	Variant summary: KIAA1033 c.2159A>G (p.Asn720Ser) results in a conservative amino acid change located in the WASH complex subunit 7, central domain (IPR028282) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 279898 control chromosomes. To our knowledge, no occurrence of c.2159A>G in individuals affected with Mental Retardation, Autosomal Recessive 43 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

WASHC4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 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

0.059

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0076

T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.037

Sift

Benign

0.32

T;.

Sift4G

Benign

0.47

T;T

Polyphen

0.0010

B;.

Vest4

0.26

MVP

0.31

MPC

0.14

ClinPred

0.040

GERP RS

6.0

Varity_R

0.080

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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