16-84326927-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021197.4(WFDC1):​c.650A>T​(p.Lys217Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 31)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11431852).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021197.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFDC1	NM_021197.4	MANE Select	c.650A>T	p.Lys217Met	missense	Exon 6 of 7	NP_067020.2
	WFDC1	NM_001282466.2		c.650A>T	p.Lys217Met	missense	Exon 6 of 7	NP_001269395.1	Q9HC57
	WFDC1	NM_001282467.2		c.647A>T	p.Lys216Met	missense	Exon 6 of 7	NP_001269396.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFDC1	ENST00000219454.10	TSL:1 MANE Select	c.650A>T	p.Lys217Met	missense	Exon 6 of 7	ENSP00000219454.5	Q9HC57
	WFDC1	ENST00000568638.1	TSL:2	c.650A>T	p.Lys217Met	missense	Exon 6 of 7	ENSP00000456920.1	Q9HC57
	WFDC1	ENST00000943489.1		c.650A>T	p.Lys217Met	missense	Exon 6 of 6	ENSP00000613548.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.047
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.45	P
Vest4		0.28
MutPred		0.21		Loss of ubiquitination at K217 (P = 0.0043)
MVP		0.33
MPC		0.021
ClinPred		0.50	D
GERP RS		1.4
Varity_R		0.12
gMVP		0.38

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;