10-50095637-A-C

Position:

• chr10-50095637-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001005751.3(WASHC2A):​c.1279A>C​(p.Met427Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,609,810 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 28)
  • Exomes 𝑓: 0.0018 (55 hom.)
• Consequence: WASHC2A NM_001005751.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.533

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00284487).
• BP6: Variant 10-50095637-A-C is Benign according to our data. Variant chr10-50095637-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3189570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2055/150910) while in subpopulation AFR AF= 0.0466 (1902/40816). AF 95% confidence interval is 0.0449. There are 41 homozygotes in gnomad4. There are 937 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC2A	NM_001005751.3	c.1279A>C	p.Met427Leu	missense_variant	15/31	ENST00000282633.10	NP_001005751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC2A	ENST00000282633.10	c.1279A>C	p.Met427Leu	missense_variant	15/31	1	NM_001005751.3	ENSP00000282633.5

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2032 AN: 150794 Hom.: 38 Cov.: 28

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00409

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000836

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000960

Gnomad OTH AF: 0.00678

GnomAD3 exomes AF: 0.00471 AC: 881 AN: 187170 Hom.: 201 AF XY: 0.00381 AC XY: 386 AN XY: 101192

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000482

Gnomad SAS exome AF: 0.000564

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000294

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.00180 AC: 2629 AN: 1458900 Hom.: 55 Cov.: 61 AF XY: 0.00164 AC XY: 1193 AN XY: 725798

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000908

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.000613

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.0136 AC: 2055 AN: 150910 Hom.: 41 Cov.: 28 AF XY: 0.0127 AC XY: 937 AN XY: 73732

Gnomad4 AFR AF: 0.0466

Gnomad4 AMR AF: 0.00408

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.000837

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.000961

Gnomad4 OTH AF: 0.00671

ExAC AF: 0.00104 AC: 76

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.10
DANN	Benign	0.36
DEOGEN2	Benign	0.0027	.;.;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00085	N
LIST_S2	Benign	0.039	T;T;T;T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.31	.;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.74	.;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0	.;B;B;B;B
Vest4		0.15
MutPred		0.065		.;Gain of methylation at K428 (P = 0.0722);Gain of methylation at K428 (P = 0.0722);Gain of methylation at K428 (P = 0.0722);.;
MVP		0.043
ClinPred		0.0017	T
GERP RS		2.8
Varity_R		0.061
gMVP		0.040

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: rs200893903; hg19: chr10-51855397; COSMIC: COSV50953394; COSMIC: COSV50953394;