20-45788963-C-G

Position:

• chr20-45788963-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000243938.9(WFDC3):​c.179G>C​(p.Gly60Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WFDC3 ENST00000243938.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

Genes affected

WFDC3 (HGNC:15957): (WAP four-disulfide core domain 3) This gene encodes a member of the WAP-type four-disulfide core (WFDC) domain family. The WFDC domain, or WAP signature motif, contains eight cysteines forming four disulfide bonds at the core of the protein, and functions as a protease inhibitor. The encoded protein contains four WFDC domains. Most WFDC genes are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the telomeric cluster. Alternatively spliced transcript variants have been observed but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30002803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC3	NM_080614.2	c.179G>C	p.Gly60Ala	missense_variant	3/7	ENST00000243938.9	NP_542181.1
WFDC3	XM_011528553.3	c.197G>C	p.Gly66Ala	missense_variant	3/7		XP_011526855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC3	ENST00000243938.9	c.179G>C	p.Gly60Ala	missense_variant	3/7	1	NM_080614.2	ENSP00000243938	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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 12, 2023

The c.179G>C (p.G60A) alteration is located in exon 3 (coding exon 2) of the WFDC3 gene. This alteration results from a G to C substitution at nucleotide position 179, causing the glycine (G) at amino acid position 60 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.81	T;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;T
Sift4G	Benign	0.37	T;T
Polyphen		0.99	D;.
Vest4		0.28
MutPred		0.56		Gain of MoRF binding (P = 0.1123);Gain of MoRF binding (P = 0.1123);
MVP		0.26
MPC		0.44
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.64
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44417602;