rs113419458

chr12-105144435-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.17

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 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. 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/exons	MANE	UniProt
WASHC4	NM_015275.3	c.2159A>G	p.Asn720Ser	missense_variant	21/33	ENST00000332180.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC4	ENST00000332180.10	c.2159A>G	p.Asn720Ser	missense_variant	21/33	1	NM_015275.3	A1

Frequencies

GnomAD3 genomes AF: 0.000285 AC: 43 AN: 150946 Hom.: 0 Cov.: 31

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: 81 AN: 249314 Hom.: 0 AF XY: 0.000333 AC XY: 45 AN XY: 135282

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.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 169 AN XY: 727072

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: 46 AN: 151036 Hom.: 0 Cov.: 31 AF XY: 0.000298 AC XY: 22 AN XY: 73792

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.: 0

Bravo AF: 0.000272

ExAC AF: 0.000364 AC: 44

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

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. -
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	- -

WASHC4-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0076	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs113419458; hg19: chr12-105538213;