16-84326927-A-G

Position:

• chr16-84326927-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021197.4(WFDC1):​c.650A>G​(p.Lys217Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,613,434 control chromosomes in the GnomAD database, including 75,716 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (7379 hom., cov: 31)
  • Exomes 𝑓: 0.30 (68337 hom.)
• Consequence: WFDC1 NM_021197.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03

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]

WFDC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004376769).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC1	NM_021197.4	c.650A>G	p.Lys217Arg	missense_variant	6/7	ENST00000219454.10	NP_067020.2
WFDC1	NM_001282466.2	c.650A>G	p.Lys217Arg	missense_variant	6/7		NP_001269395.1
WFDC1	NM_001282467.2	c.647A>G	p.Lys216Arg	missense_variant	6/7		NP_001269396.1
WFDC1	XM_047434411.1	c.566A>G	p.Lys189Arg	missense_variant	5/6		XP_047290367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC1	ENST00000219454.10	c.650A>G	p.Lys217Arg	missense_variant	6/7	1	NM_021197.4	ENSP00000219454.5
WFDC1	ENST00000568638.1	c.650A>G	p.Lys217Arg	missense_variant	6/7	2		ENSP00000456920.1
WFDC1	ENST00000567056.1	n.3603A>G		non_coding_transcript_exon_variant	3/4	2
WFDC1	ENST00000622779.1	n.1264A>G		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46908 AN: 151706 Hom.: 7372 Cov.: 31

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.302

GnomAD3 exomes AF: 0.284 AC: 71431 AN: 251410 Hom.: 10411 AF XY: 0.286 AC XY: 38833 AN XY: 135870

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.253

Gnomad SAS exome AF: 0.304

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.304 AC: 443934 AN: 1461610 Hom.: 68337 Cov.: 36 AF XY: 0.303 AC XY: 220456 AN XY: 727116

Gnomad4 AFR exome AF: 0.336

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.237

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.309 AC: 46947 AN: 151824 Hom.: 7379 Cov.: 31 AF XY: 0.309 AC XY: 22956 AN XY: 74176

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.304

Alfa AF: 0.302 Hom.: 17869

Bravo AF: 0.312

TwinsUK AF: 0.324 AC: 1200

ALSPAC AF: 0.332 AC: 1278

ESP6500AA AF: 0.328 AC: 1442

ESP6500EA AF: 0.309 AC: 2654

ExAC AF: 0.284 AC: 34535

Asia WGS AF: 0.327 AC: 1136 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.297

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.056
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.28	.;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.71	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.017
MPC		0.019
ClinPred		0.00073	T
GERP RS		1.4
Varity_R		0.027
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12933084; hg19: chr16-84360533; COSMIC: COSV54742919;