chr9-14884-C-T

Variant names:

• chr9-14884-C-T
• rs750650734
• NM_001378090.1:c.1321G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001378090.1(WASHC1):​c.1321G>A​(p.Val441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 124,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000024 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: WASHC1 NM_001378090.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.55
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0584749).
• BP6: Variant 9-14884-C-T is Benign according to our data. Variant chr9-14884-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2515670.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1321G>A	p.Val441Met	missense	Exon 11 of 11	NP_001365019.1	A8K0Z3
	WASHC1	NM_182905.6		c.1321G>A	p.Val441Met	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.1321G>A	p.Val441Met	missense	Exon 11 of 11	ENSP00000512441.1	A8K0Z3
	WASHC1	ENST00000442898.5	TSL:2	c.1321G>A	p.Val441Met	missense	Exon 11 of 11	ENSP00000485627.1	A8K0Z3

Frequencies

GnomAD3 genomes AF: 0.0000160 AC: 2 AN: 124732 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000411

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000538 AC: 10 AN: 186004 AF XY: 0.0000788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000355

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000243 AC: 30 AN: 1236582 Hom.: 1 Cov.: 37 AF XY: 0.0000259 AC XY: 16 AN XY: 617300

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

African (AFR) AF: 0.000101 AC: 2 AN: 19738

American (AMR) AF: 0.0000769 AC: 3 AN: 39030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22374

East Asian (EAS) AF: 0.000139 AC: 5 AN: 35854

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3432

European-Non Finnish (NFE) AF: 0.0000170 AC: 16 AN: 943854

Other (OTH) AF: 0.0000589 AC: 3 AN: 50968

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000398295), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000160 AC: 2 AN: 124782 Hom.: 0 Cov.: 24 AF XY: 0.0000329 AC XY: 2 AN XY: 60818

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

African (AFR) AF: 0.00 AC: 0 AN: 27674

American (AMR) AF: 0.00 AC: 0 AN: 13032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3072

East Asian (EAS) AF: 0.000412 AC: 2 AN: 4856

South Asian (SAS) AF: 0.00 AC: 0 AN: 4118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60068

Other (OTH) AF: 0.00 AC: 0 AN: 1784

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000310 AC: 3

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.5
DANN	Benign	0.95
DEOGEN2	Benign	0.018	T
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.058	T
MutationAssessor	Benign	-1.8	N
PhyloP100		3.6
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.21
GERP RS		0.0057
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.020
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs750650734; hg19: chr9-14884; COSMIC: COSV57924594; COSMIC: COSV57924594;