10-45750127-A-T

Position:

• chr10-45750127-A-T

Variant summary

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

The NM_001367406.1(WASHC2C):​c.-957A>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: WASHC2C NM_001367406.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39

Genes affected

WASHC2C (HGNC:23414): (WASH complex subunit 2C) Enables phosphatidylinositol phosphate binding activity; phosphatidylinositol-3,4-bisphosphate binding activity; and retromer complex binding activity. Involved in several processes, including endosomal transport; negative regulation of barbed-end actin filament capping; and regulation of substrate adhesion-dependent cell spreading. Located in cytosol; early endosome; and nucleolus. Part of WASH complex. [provided by Alliance of Genome Resources, Apr 2022]

WASHC2C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC2C	NM_001330074.2	c.764A>T	p.Asp255Val	missense_variant	9/31	ENST00000623400.4	NP_001317003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC2C	ENST00000623400.4	c.764A>T	p.Asp255Val	missense_variant	9/31	1	NM_001330074.2	ENSP00000485513.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.764A>T (p.D255V) alteration is located in exon 9 (coding exon 9) of the FAM21C gene. This alteration results from a A to T substitution at nucleotide position 764, causing the aspartic acid (D) at amino acid position 255 to be replaced by a valine (V). 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	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D;D;D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.
Vest4		0.41
MutPred		0.53		.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;
MVP		0.57
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.57
gMVP		0.090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-46245575;