9-15962-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC1	NM_001378090.1	c.1142G>A	p.Arg381His	missense_variant	Exon 9 of 11	ENST00000696149.1	NP_001365019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC1	ENST00000696149.1	c.1142G>A	p.Arg381His	missense_variant	Exon 9 of 11		NM_001378090.1	ENSP00000512441.1
WASHC1	ENST00000442898.5	c.1142G>A	p.Arg381His	missense_variant	Exon 9 of 11	2		ENSP00000485627.1
WASHC1	ENST00000696150.1	n.1406G>A		non_coding_transcript_exon_variant	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

GnomAD3 exomes AF: 0.0000892 AC: 12 AN: 134458 Hom.: 0 AF XY: 0.000109 AC XY: 8 AN XY: 73082

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 SAS exome AF: 0.000320

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

Gnomad4 AFR exome AF: 0.000728

Gnomad4 AMR exome AF: 0.000126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000294

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000545

Gnomad4 OTH exome AF: 0.0000819

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

Gnomad4 AFR AF: 0.000151

Gnomad4 AMR AF: 0.0000704

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000227

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000126

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000612 Hom.: 0

ExAC AF: 0.0000533 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1142G>A (p.R381H) alteration is located in exon 9 (coding exon 8) of the WASH1 gene. This alteration results from a G to A substitution at nucleotide position 1142, causing the arginine (R) at amino acid position 381 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs775786649; hg19: chr9-15962;