Genetic Variant WASHC1:p.Arg440His (chr9-14886-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001378090.1(WASHC1):c.1319G>A(p.Arg440His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,359,608 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 2 hom., cov: 24)

Exomes 𝑓: 0.000049 ( 3 hom. )

Consequence

WASHC1
NM_001378090.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.79

Variant links:

Genes affected

WASHC1 (HGNC:24361): (WASH complex subunit 1) Enables alpha-tubulin binding activity and ubiquitin protein ligase binding activity. Involved in several processes, including Arp2/3 complex-mediated actin nucleation; endosomal transport; and positive regulation of pseudopodium assembly. Located in early endosome. Part of WASH complex. Colocalizes with exocyst. [provided by Alliance of Genome Resources, Apr 2022]

WASHC1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042898).

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC1	NM_001378090.1 link	c.1319G>A	p.Arg440His	missense_variant	Exon 11 of 11	ENST00000696149.1	NP_001365019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC1	ENST00000696149.1 link	c.1319G>A	p.Arg440His	missense_variant	Exon 11 of 11		NM_001378090.1	ENSP00000512441.1		A8K0Z3
WASHC1	ENST00000442898.5 link	c.1319G>A	p.Arg440His	missense_variant	Exon 11 of 11	2		ENSP00000485627.1		A8K0Z3

Frequencies

GnomAD3 genomes

AF:

0.000474

AC:

AN:

124538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000384

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:

0.0000500

Gnomad OTH

AF:

0.000569

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

183546

Hom.:

AF XY:

0.0000600

AC XY:

AN XY:

100052

show subpopulations

Gnomad AFR exome

AF:

0.000697

Gnomad AMR exome

AF:

0.0000356

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:

0.0000241

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1235020

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

616490

show subpopulations

Gnomad4 AFR exome

AF:

0.00153

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000836

Gnomad4 SAS exome

AF:

0.0000940

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000148

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.000474

AC:

AN:

124588

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

AN XY:

60700

show subpopulations

Gnomad4 AFR

AF:

0.00182

Gnomad4 AMR

AF:

0.000384

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000500

Gnomad4 OTH

AF:

0.000562

Alfa

AF:

0.000291

Hom.:

ExAC

AF:

0.0000311

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1319G>A (p.R440H) alteration is located in exon 11 (coding exon 10) of the WASH1 gene. This alteration results from a G to A substitution at nucleotide position 1319, causing the arginine (R) at amino acid position 440 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.82

MetaRNN

Benign

0.043

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.72

Sift4G

Benign

0.083

Polyphen

0.0090

Vest4

0.49

MVP

0.23

GERP RS

1.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.028

gMVP

0.29

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