9-14821-C-A

Variant names:

• chr9-14821-C-A
• rs761521000
• NM_001378090.1:c.1384G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378090.1(WASHC1):​c.1384G>T​(p.Asp462Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D462N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WASHC1 NM_001378090.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

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.1384G>T	p.Asp462Tyr	missense	Exon 11 of 11	NP_001365019.1	A8K0Z3
	WASHC1	NM_182905.6		c.1384G>T	p.Asp462Tyr	missense	Exon 11 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.1384G>T	p.Asp462Tyr	missense	Exon 11 of 11	ENSP00000512441.1	A8K0Z3
	WASHC1	ENST00000442898.5	TSL:2	c.1384G>T	p.Asp462Tyr	missense	Exon 11 of 11	ENSP00000485627.1	A8K0Z3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 209080 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000144 AC: 2 AN: 1384750 Hom.: 0 Cov.: 39 AF XY: 0.00000145 AC XY: 1 AN XY: 690444

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

African (AFR) AF: 0.00 AC: 0 AN: 30298

American (AMR) AF: 0.00 AC: 0 AN: 43470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24744

East Asian (EAS) AF: 0.00 AC: 0 AN: 39168

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3906

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051876

Other (OTH) AF: 0.0000175 AC: 1 AN: 57152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.5
PrimateAI	Uncertain	0.65	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.55
GERP RS		1.2
Varity_R		0.067
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs761521000; hg19: chr9-14821;