10-50093355-G-T

Variant names:

• chr10-50093355-G-T
• rs531366998
• NM_001005751.3:c.1091G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001005751.3(WASHC2A):​c.1091G>T​(p.Gly364Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 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. G364D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000031 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WASHC2A NM_001005751.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60
• Publications: 0 publications found

Genes affected

WASHC2A (HGNC:23416): (WASH complex subunit 2A) Predicted to enable phosphatidylinositol phosphate binding activity and retromer complex binding activity. Involved in protein localization to endosome. Located in cytosol and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2660671).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005751.3. 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
	WASHC2A	NM_001005751.3	MANE Select	c.1091G>T	p.Gly364Val	missense	Exon 12 of 31	NP_001005751.1	Q641Q2-1
	WASHC2A	NM_001291398.2		c.1091G>T	p.Gly364Val	missense	Exon 12 of 30	NP_001278327.1	Q641Q2-2
	WASHC2A	NM_001437388.1		c.1019G>T	p.Gly340Val	missense	Exon 11 of 30	NP_001424317.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC2A	ENST00000282633.10	TSL:1 MANE Select	c.1091G>T	p.Gly364Val	missense	Exon 12 of 31	ENSP00000282633.5	Q641Q2-1
	WASHC2A	ENST00000351071.11	TSL:1	c.1091G>T	p.Gly364Val	missense	Exon 12 of 30	ENSP00000344037.6	Q641Q2-2
	WASHC2A	ENST00000314664.12	TSL:1	c.1091G>T	p.Gly364Val	missense	Exon 12 of 29	ENSP00000314417.7	E7ESD2

Frequencies

GnomAD3 genomes AF: 0.0000308 AC: 4 AN: 129978 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000706

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000104 AC: 137 AN: 1317246 Hom.: 0 Cov.: 29 AF XY: 0.0000943 AC XY: 62 AN XY: 657268

African (AFR) AF: 0.00 AC: 0 AN: 32918

American (AMR) AF: 0.000128 AC: 5 AN: 39000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000607 AC: 5 AN: 82316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3616

European-Non Finnish (NFE) AF: 0.000121 AC: 120 AN: 990750

Other (OTH) AF: 0.000127 AC: 7 AN: 55142

GnomAD4 genome AF: 0.0000307 AC: 4 AN: 130086 Hom.: 0 Cov.: 17 AF XY: 0.0000318 AC XY: 2 AN XY: 62938

⚠️ 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: 38984

American (AMR) AF: 0.00 AC: 0 AN: 11464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2764

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 3962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.0000706 AC: 4 AN: 56634

Other (OTH) AF: 0.00 AC: 0 AN: 1726

⚠️ 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

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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.12	T
PhyloP100		7.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.24		Gain of methylation at K365 (P = 0.0334)
MVP		0.15
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.17
Mutation Taster		=92/8	polymorphism

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: rs531366998; hg19: chr10-51853115;