10-50093881-C-T

Variant names:

• chr10-50093881-C-T
• rs1157827955
• NM_001005751.3:c.1144C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005751.3(WASHC2A):​c.1144C>T​(p.Pro382Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000723 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WASHC2A NM_001005751.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.763

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08005577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC2A	NM_001005751.3	c.1144C>T	p.Pro382Ser	missense_variant	Exon 13 of 31	ENST00000282633.10	NP_001005751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC2A	ENST00000282633.10	c.1144C>T	p.Pro382Ser	missense_variant	Exon 13 of 31	1	NM_001005751.3	ENSP00000282633.5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152042 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000206 AC: 3 AN: 1458080 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725416

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152158 Hom.: 0 Cov.: 28 AF XY: 0.000134 AC XY: 10 AN XY: 74372

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1144C>T (p.P382S) alteration is located in exon 13 (coding exon 13) of the FAM21A gene. This alteration results from a C to T substitution at nucleotide position 1144, causing the proline (P) at amino acid position 382 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	0.096
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.16	.;.;T;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.080	T;T;T;T;T
MetaSVM	Benign	-0.75	T
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.5	.;D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.11	.;T;T;T;T
Sift4G	Uncertain	0.044	D;D;D;D;D
Polyphen		0.049, 1.0	.;B;B;B;D
Vest4		0.11
MutPred		0.18		.;Gain of phosphorylation at P382 (P = 0.0148);Gain of phosphorylation at P382 (P = 0.0148);Gain of phosphorylation at P382 (P = 0.0148);.;
MVP		0.15
ClinPred		0.086	T
GERP RS		3.9
Varity_R		0.095
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1157827955; hg19: chr10-51853641;