Genetic Variant WASHC2A:p.Pro17Ser (chr10-50068150-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001005751.3(WASHC2A):c.49C>T(p.Pro17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000518 in 1,602,520 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 2 hom., cov: 30)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

WASHC2A
NM_001005751.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.886

Variant links:

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]

WASHC2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02248305).

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC2A	NM_001005751.3 link	c.49C>T	p.Pro17Ser	missense_variant	Exon 2 of 31	ENST00000282633.10	NP_001005751.1	Q641Q2-1Q6P0Q7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC2A	ENST00000282633.10 link	c.49C>T	p.Pro17Ser	missense_variant	Exon 2 of 31	1	NM_001005751.3	ENSP00000282633.5		Q641Q2-1

Frequencies

GnomAD3 genomes

AF:

0.000338

AC:

AN:

148094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

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:

0.00

Gnomad OTH

AF:

0.000495

GnomAD3 exomes

AF:

0.0000904

AC:

AN:

232186

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

127412

show subpopulations

Gnomad AFR exome

AF:

0.00158

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1454316

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

723282

show subpopulations

Gnomad4 AFR exome

AF:

0.000963

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.000337

AC:

AN:

148204

Hom.:

Cov.:

AF XY:

0.000373

AC XY:

AN XY:

72382

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000489

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.000291

ESP6500AA

AF:

0.00139

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000118

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49C>T (p.P17S) alteration is located in exon 2 (coding exon 2) of the FAM21A gene. This alteration results from a C to T substitution at nucleotide position 49, causing the proline (P) at amino acid position 17 to be replaced by a serine (S). 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

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

.;.;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.022

T;T;T;T

MetaSVM

Benign

-0.59

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.9

.;D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.010

.;D;D;D

Sift4G

Uncertain

0.049

D;D;D;D

Polyphen

0.45, 0.83, 0.72

.;B;P;P

Vest4

0.28

MVP

0.043

ClinPred

0.10

GERP RS

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over