chr16-84326927-A-G

Variant names:

• chr16-84326927-A-G
• rs12933084
• NM_021197.4:c.650A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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: 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
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
WFDC1	NM_021197.4	c.650A>G	p.Lys217Arg	missense_variant	Exon 6 of 7	ENST00000219454.10	NP_067020.2
WFDC1	NM_001282466.2	c.650A>G	p.Lys217Arg	missense_variant	Exon 6 of 7		NP_001269395.1
WFDC1	NM_001282467.2	c.647A>G	p.Lys216Arg	missense_variant	Exon 6 of 7		NP_001269396.1
WFDC1	XM_047434411.1	c.566A>G	p.Lys189Arg	missense_variant	Exon 5 of 6		XP_047290367.1

Ensembl

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

GnomAD2 exomes AF: 0.284 AC: 71431 AN: 251410 AF XY: 0.286

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 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

African (AFR) AF: 0.336 AC: 11260 AN: 33474

American (AMR) AF: 0.264 AC: 11821 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6560 AN: 26132

East Asian (EAS) AF: 0.237 AC: 9402 AN: 39696

South Asian (SAS) AF: 0.309 AC: 26666 AN: 86244

European-Finnish (FIN) AF: 0.249 AC: 13298 AN: 53408

Middle Eastern (MID) AF: 0.247 AC: 1422 AN: 5768

European-Non Finnish (NFE) AF: 0.310 AC: 345057 AN: 1111802

Other (OTH) AF: 0.306 AC: 18448 AN: 60376

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

African (AFR) AF: 0.342 AC: 14129 AN: 41372

American (AMR) AF: 0.319 AC: 4876 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3470

East Asian (EAS) AF: 0.253 AC: 1293 AN: 5118

South Asian (SAS) AF: 0.305 AC: 1467 AN: 4802

European-Finnish (FIN) AF: 0.253 AC: 2664 AN: 10546

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20739 AN: 67936

Other (OTH) AF: 0.304 AC: 640 AN: 2106

Alfa AF: 0.303 Hom.: 35090

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
PhyloP100		1.0
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12933084; hg19: chr16-84360533; COSMIC: COSV54742919;