20-45562211-G-A

Position:

• chr20-45562211-G-A

Variant summary

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

The NM_130896.3(WFDC8):​c.35C>T​(p.Pro12Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WFDC8 NM_130896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.565

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=0.11000115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC8	NM_130896.3	c.35C>T	p.Pro12Leu	missense_variant	2/6	ENST00000289953.3	NP_570966.2
WFDC8	NM_181510.3	c.35C>T	p.Pro12Leu	missense_variant	2/7		NP_852611.2
WFDC8	XM_017028119.2	c.35C>T	p.Pro12Leu	missense_variant	2/5		XP_016883608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC8	ENST00000289953.3	c.35C>T	p.Pro12Leu	missense_variant	2/6	1	NM_130896.3	ENSP00000289953.2
WFDC8	ENST00000357199.8	c.35C>T	p.Pro12Leu	missense_variant	2/7	1		ENSP00000361735.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 09, 2024

The c.35C>T (p.P12L) alteration is located in exon 2 (coding exon 2) of the WFDC8 gene. This alteration results from a C to T substitution at nucleotide position 35, causing the proline (P) at amino acid position 12 to be replaced by a leucine (L). 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	0.099
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0064	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.53	.;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.012
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.20	B;B
Vest4		0.18
MutPred		0.44		Gain of catalytic residue at P12 (P = 0.0026);Gain of catalytic residue at P12 (P = 0.0026);
MVP		0.25
MPC		0.20
ClinPred		0.33	T
GERP RS		0.69
Varity_R		0.089
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44190850; COSMIC: COSV51491240; COSMIC: COSV51491240;