chr20-45552040-C-G

Variant names:

• chr20-45552040-C-G
• rs1980051713
• NM_130896.3:c.712G>C

Variant summary

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

The NM_130896.3(WFDC8):​c.712G>C​(p.Asp238His) 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. 16/21 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: WFDC8 NM_130896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.306

Genes affected

WFDC8 (HGNC:16163): (WAP four-disulfide core domain 8) 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 a Kunitz-inhibitor domain, in addition to three WFDC domains. Most WFDC genes are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the telomeric cluster. Two alternatively spliced transcript variants have been found for this gene, and they encode the same protein. [provided by RefSeq, Jul 2008]

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=0.22271028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFDC8	NM_130896.3	c.712G>C	p.Asp238His	missense_variant	Exon 6 of 6	ENST00000289953.3	NP_570966.2
WFDC8	NM_181510.3	c.712G>C	p.Asp238His	missense_variant	Exon 6 of 7		NP_852611.2
WFDC8	XM_017028119.2	c.*938G>C		downstream_gene_variant			XP_016883608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFDC8	ENST00000289953.3	c.712G>C	p.Asp238His	missense_variant	Exon 6 of 6	1	NM_130896.3	ENSP00000289953.2
WFDC8	ENST00000357199.8	c.712G>C	p.Asp238His	missense_variant	Exon 6 of 7	1		ENSP00000361735.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.712G>C (p.D238H) alteration is located in exon 6 (coding exon 6) of the WFDC8 gene. This alteration results from a G to C substitution at nucleotide position 712, causing the aspartic acid (D) at amino acid position 238 to be replaced by a histidine (H). 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	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.3
DANN	Benign	0.47
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.26	.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.19
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.74	P;P
Vest4		0.14
MutPred		0.39		Loss of ubiquitination at K235 (P = 0.0228);Loss of ubiquitination at K235 (P = 0.0228);
MVP		0.41
MPC		0.16
ClinPred		0.33	T
GERP RS		-3.4
Varity_R		0.038
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1980051713; hg19: chr20-44180679; COSMIC: COSV51489247; COSMIC: COSV51489247;