rs113168943

chr12-105164239-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_015275.3(WASHC4):c.3286G>A(p.Ala1096Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. A1096V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0210

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006246686).
• BP6: Variant 12-105164239-G-A is Benign according to our data. Variant chr12-105164239-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435589.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000404 (59/1461758) while in subpopulation AFR AF= 0.00114 (38/33478). AF 95% confidence interval is 0.000849. There are 0 homozygotes in gnomad4_exome. There are 30 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASHC4	NM_015275.3	c.3286G>A	p.Ala1096Thr	missense_variant	31/33	ENST00000332180.10
WASHC4	NM_001293640.2	c.3289G>A	p.Ala1097Thr	missense_variant	31/33
WASHC4	XM_011538073.4	c.3151G>A	p.Ala1051Thr	missense_variant	30/32
WASHC4	XM_011538074.3	c.2722G>A	p.Ala908Thr	missense_variant	25/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC4	ENST00000332180.10	c.3286G>A	p.Ala1096Thr	missense_variant	31/33	1	NM_015275.3	A1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000478

GnomAD3 exomes AF: 0.0000522 AC: 13 AN: 249260 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135228

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727174

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74464

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.0000653

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: 0.000473

Alfa AF: 0.000187 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

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.3286G>A (p.Ala1096Thr) results in a non-conservative amino acid change located in the WASH complex subunit 7, C-terminal domain (IPR028283) 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 6.1e-05 in 280666 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3286G>A 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 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 05, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.21
Dann	Benign	0.47
DEOGEN2	Benign	0.086	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.15	N;.
REVEL	Benign	0.17
Sift	Benign	0.69	T;.
Sift4G	Benign	0.58	T;T
Polyphen		0.0	B;.
Vest4		0.050
MVP		0.19
MPC		0.17
ClinPred		0.0044	T
GERP RS		-6.3
Varity_R		0.024
gMVP		0.12

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: rs113168943; hg19: chr12-105558017;