chr20-45702205-G-A

Position:

• chr20-45702205-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172005.2(WFDC13):​c.82G>A​(p.Val28Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WFDC13 NM_172005.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.731

Genes affected

WFDC13 (HGNC:16131): (WAP four-disulfide core domain 13) 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. Most WFDC gene members are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the telomeric cluster. [provided by RefSeq, Jul 2008]

WFDC10B (HGNC:20479): (WAP four-disulfide core domain 10B) 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. Most WFDC gene members 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 distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047252446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFDC13	NM_172005.2	c.82G>A	p.Val28Ile	missense_variant	1/4	ENST00000305479.3
WFDC10B	NM_172006.2	c.-65+2292C>T		intron_variant		ENST00000330523.10
WFDC10B	NM_172131.2	c.139+2292C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFDC13	ENST00000305479.3	c.82G>A	p.Val28Ile	missense_variant	1/4	1	NM_172005.2	P1
WFDC10B	ENST00000330523.10	c.-65+2292C>T		intron_variant		1	NM_172006.2	P1
WFDC10B	ENST00000335769.2	c.139+2292C>T		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459628 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Dec 20, 2023

The c.82G>A (p.V28I) alteration is located in exon 1 (coding exon 1) of the WFDC13 gene. This alteration results from a G to A substitution at nucleotide position 82, causing the valine (V) at amino acid position 28 to be replaced by an isoleucine (I). 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	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.13
DANN	Benign	0.60
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.062
Sift	Benign	0.40	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.025
MutPred		0.17		Loss of sheet (P = 0.0457);
MVP		0.014
MPC		0.034
ClinPred		0.090	T
GERP RS		-5.9
Varity_R		0.018
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr20-44330844;