chr9-15962-C-T

Variant names:

• chr9-15962-C-T
• rs775786649
• NM_001378090.1:c.1142G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378090.1(WASHC1):​c.1142G>A​(p.Arg381His) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 136,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R381C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000082 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: WASHC1 NM_001378090.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378090.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC1	NM_001378090.1	MANE Select	c.1142G>A	p.Arg381His	missense	Exon 9 of 11	NP_001365019.1	A8K0Z3
	WASHC1	NM_182905.6		c.1142G>A	p.Arg381His	missense	Exon 9 of 11	NP_878908.4	A8K0Z3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC1	ENST00000696149.1	MANE Select	c.1142G>A	p.Arg381His	missense	Exon 9 of 11	ENSP00000512441.1	A8K0Z3
	WASHC1	ENST00000442898.5	TSL:2	c.1142G>A	p.Arg381His	missense	Exon 9 of 11	ENSP00000485627.1	A8K0Z3
	WASHC1	ENST00000696150.1		n.1406G>A		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.000110 AC: 15 AN: 136218 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000705

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000126

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000892 AC: 12 AN: 134458 AF XY: 0.000109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000444

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000845

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000723

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000824 AC: 94 AN: 1140818 Hom.: 2 Cov.: 21 AF XY: 0.0000834 AC XY: 48 AN XY: 575600

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000728 AC: 16 AN: 21982

American (AMR) AF: 0.000126 AC: 5 AN: 39538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23100

East Asian (EAS) AF: 0.00 AC: 0 AN: 37312

South Asian (SAS) AF: 0.000294 AC: 22 AN: 74834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47444

Middle Eastern (MID) AF: 0.000292 AC: 1 AN: 3420

European-Non Finnish (NFE) AF: 0.0000545 AC: 46 AN: 844342

Other (OTH) AF: 0.0000819 AC: 4 AN: 48846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000180966), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000110 AC: 15 AN: 136300 Hom.: 0 Cov.: 24 AF XY: 0.0000754 AC XY: 5 AN XY: 66298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000151 AC: 5 AN: 33128

American (AMR) AF: 0.0000704 AC: 1 AN: 14196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3230

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.000227 AC: 1 AN: 4412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000126 AC: 8 AN: 63472

Other (OTH) AF: 0.00 AC: 0 AN: 1884

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000117268), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000612 Hom.: 0

ExAC AF: 0.0000533 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
MetaRNN	Uncertain	0.74	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.9
PrimateAI	Uncertain	0.75	T
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.78
MVP		0.26
GERP RS		1.3
Varity_R		0.035
gMVP		0.44

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

Other links and lift over

dbSNP: rs775786649; hg19: chr9-15962;