16-84294987-G-A

Position:

• chr16-84294987-G-A

Variant summary

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

The NM_021197.4(WFDC1):​c.16G>A​(p.Val6Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,613,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: WFDC1 NM_021197.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.69

Genes affected

WFDC1 (HGNC:15466): (WAP four-disulfide core domain 1) This gene encodes a member of the WAP-type four disulfide core domain family. The WAP-type four-disulfide core domain contains eight cysteines forming four disulfide bonds at the core of the protein, and functions as a protease inhibitor in many family members. This gene is mapped to chromosome 16q24, an area of frequent loss of heterozygosity in cancers, including prostate, breast and hepatocellular cancers and Wilms' tumor. This gene is downregulated in many cancer types and may be involved in the inhibition of cell proliferation. The encoded protein may also play a role in the susceptibility of certain CD4 memory T cells to human immunodeficiency virus infection. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

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=0.02744016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC1	NM_021197.4	c.16G>A	p.Val6Met	missense_variant	1/7	ENST00000219454.10	NP_067020.2
WFDC1	NM_001282466.2	c.16G>A	p.Val6Met	missense_variant	1/7		NP_001269395.1
WFDC1	NM_001282467.2	c.16G>A	p.Val6Met	missense_variant	1/7		NP_001269396.1
WFDC1	XM_047434411.1	c.16G>A	p.Val6Met	missense_variant	1/6		XP_047290367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC1	ENST00000219454.10	c.16G>A	p.Val6Met	missense_variant	1/7	1	NM_021197.4	ENSP00000219454.5
WFDC1	ENST00000568638.1	c.16G>A	p.Val6Met	missense_variant	1/7	2		ENSP00000456920.1
WFDC1	ENST00000613603.1	c.16G>A	p.Val6Met	missense_variant	1/1	6		ENSP00000481580.1

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152268 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 250586 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135476

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000190 AC: 277 AN: 1461338 Hom.: 1 Cov.: 31 AF XY: 0.000180 AC XY: 131 AN XY: 726932

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152268 Hom.: 0 Cov.: 34 AF XY: 0.000255 AC XY: 19 AN XY: 74390

Gnomad4 AFR AF: 0.000651

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000190 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2024

The c.16G>A (p.V6M) alteration is located in exon 1 (coding exon 1) of the WFDC1 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the valine (V) at amino acid position 6 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.5
DANN	Benign	0.92
DEOGEN2	Benign	0.023	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.56	.;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.020	N;N;.
REVEL	Benign	0.022
Sift	Benign	0.095	T;T;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.31	B;B;.
Vest4		0.12
MVP		0.014
MPC		0.021
ClinPred		0.0091	T
GERP RS		-8.2
Varity_R		0.030
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs143040901; hg19: chr16-84328593;