rs200763691

chr12-105126083-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015275.3(WASHC4):c.866C>T(p.Ala289Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,612,908 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0106163025).
• BP6: Variant 12-105126083-C-T is Benign according to our data. Variant chr12-105126083-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 435575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0017 (259/152180) while in subpopulation AFR AF= 0.00616 (256/41570). AF 95% confidence interval is 0.00554. There are 3 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASHC4	NM_015275.3	c.866C>T	p.Ala289Val	missense_variant	11/33	ENST00000332180.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC4	ENST00000332180.10	c.866C>T	p.Ala289Val	missense_variant	11/33	1	NM_015275.3	A1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152062 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000434 AC: 108 AN: 248572 Hom.: 2 AF XY: 0.000334 AC XY: 45 AN XY: 134860

Gnomad AFR exome AF: 0.00623

Gnomad AMR exome AF: 0.000291

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: 0.00000887

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000173 AC: 252 AN: 1460728 Hom.: 2 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 726674

Gnomad4 AFR exome AF: 0.00655

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152180 Hom.: 3 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74384

Gnomad4 AFR AF: 0.00616

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000855 Hom.: 1

Bravo AF: 0.00211

ESP6500AA AF: 0.00658 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000513 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

WASHC4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2019

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	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0037	T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.50	N;.
REVEL	Benign	0.18
Sift	Benign	1.0	T;.
Sift4G	Benign	0.41	T;T
Polyphen		0.21	B;.
Vest4		0.83
MVP		0.46
MPC		0.26
ClinPred		0.049	T
GERP RS		5.6
Varity_R		0.13
gMVP		0.50

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

Other links and lift over

dbSNP: rs200763691; hg19: chr12-105519861; COSMIC: COSV99046037; COSMIC: COSV99046037;