16-84318346-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_021197.4(WFDC1):c.412G>A(p.Val138Met) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,614,024 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 6 hom., cov: 33)

Exomes 𝑓: 0.012 ( 133 hom. )

Consequence

WFDC1
NM_021197.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.07

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010461688).

BP6

Variant 16-84318346-G-A is Benign according to our data. Variant chr16-84318346-G-A is described in ClinVar as [Benign]. Clinvar id is 774721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFDC1	NM_021197.4 link	c.412G>A	p.Val138Met	missense_variant	Exon 3 of 7	ENST00000219454.10	NP_067020.2	Q9HC57
WFDC1	NM_001282466.2 link	c.412G>A	p.Val138Met	missense_variant	Exon 3 of 7		NP_001269395.1	Q9HC57
WFDC1	NM_001282467.2 link	c.412G>A	p.Val138Met	missense_variant	Exon 3 of 7		NP_001269396.1	Q9HC57
WFDC1	XM_047434411.1 link	c.338-1085G>A		intron_variant	Intron 2 of 5		XP_047290367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WFDC1	ENST00000219454.10 link	c.412G>A	p.Val138Met	missense_variant	Exon 3 of 7	1	NM_021197.4	ENSP00000219454.5	Q9HC57
WFDC1	ENST00000568638.1 link	c.412G>A	p.Val138Met	missense_variant	Exon 3 of 7	2		ENSP00000456920.1	Q9HC57
WFDC1	ENST00000567056.1 link	n.2290G>A		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00831

AC:

1264

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00903

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00880

AC:

2212

AN:

251282

AF XY:

0.00881

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00668

Gnomad ASJ exome

AF:

0.0258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.0117

AC:

17058

AN:

1461724

Hom.:

133

Cov.:

AF XY:

0.0114

AC XY:

8308

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33478

American (AMR)

AF:

0.00646

AC:

289

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0261

AC:

681

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00163

AC:

141

AN:

86252

European-Finnish (FIN)

AF:

0.00341

AC:

182

AN:

53412

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0135

AC:

14964

AN:

1111904

Other (OTH)

AF:

0.0112

AC:

679

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

818

1636

2455

3273

4091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00830

AC:

1264

AN:

152300

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

560

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41568

American (AMR)

AF:

0.00902

AC:

138

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00269

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0127

AC:

861

AN:

68018

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

133

199

266

332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.00838

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0141

AC:

121

ExAC

AF:

0.00932

AC:

1131

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

.;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;L

PhyloP100

5.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.88

P;P

Vest4

0.59

MVP

0.20

MPC

0.047

ClinPred

0.042

GERP RS

3.0

Varity_R

0.11

gMVP

0.44

Mutation Taster

=100/0

polymorphism

(source)

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

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16-84318346-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over