16-84313110-C-G

Position:

• chr16-84313110-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021197.4(WFDC1):​c.294C>G​(p.Asn98Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000853 in 1,289,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: WFDC1 NM_021197.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.18

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC1	NM_021197.4	c.294C>G	p.Asn98Lys	missense_variant	2/7	ENST00000219454.10	NP_067020.2
WFDC1	NM_001282466.2	c.294C>G	p.Asn98Lys	missense_variant	2/7		NP_001269395.1
WFDC1	NM_001282467.2	c.294C>G	p.Asn98Lys	missense_variant	2/7		NP_001269396.1
WFDC1	XM_047434411.1	c.294C>G	p.Asn98Lys	missense_variant	2/6		XP_047290367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC1	ENST00000219454.10	c.294C>G	p.Asn98Lys	missense_variant	2/7	1	NM_021197.4	ENSP00000219454.5
WFDC1	ENST00000568638.1	c.294C>G	p.Asn98Lys	missense_variant	2/7	2		ENSP00000456920.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000853 AC: 11 AN: 1289420 Hom.: 0 Cov.: 30 AF XY: 0.00000945 AC XY: 6 AN XY: 634596

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000106

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

Mar 18, 2024

The c.294C>G (p.N98K) alteration is located in exon 2 (coding exon 2) of the WFDC1 gene. This alteration results from a C to G substitution at nucleotide position 294, causing the asparagine (N) at amino acid position 98 to be replaced by a lysine (K). 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	0.030
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.81		Gain of methylation at N98 (P = 0.0016);Gain of methylation at N98 (P = 0.0016);
MVP		0.58
MPC		0.17
ClinPred		1.0	D
GERP RS		-1.6
Varity_R		0.90
gMVP		0.89

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: chr16-84346716;