Genetic Variant NM_130896.3:c.-125G>A (chr20-45579372-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_130896.3(WFDC8):c.-125G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,275,030 control chromosomes in the GnomAD database, including 96,391 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 9352 hom., cov: 31)

Exomes 𝑓: 0.38 ( 87039 hom. )

Consequence

WFDC8
NM_130896.3 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.311

Publications

5 publications found

Variant links:

COSMIC-nc: COSV51489582

Genes affected

WFDC8 (HGNC:16163): (WAP four-disulfide core domain 8) This gene encodes a member of the WAP-type four-disulfide core (WFDC) domain family. The WFDC domain, or WAP signature motif, contains eight cysteines forming four disulfide bonds at the core of the protein, and functions as a protease inhibitor. The encoded protein contains a Kunitz-inhibitor domain, in addition to three WFDC domains. Most WFDC genes are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the telomeric cluster. Two alternatively spliced transcript variants have been found for this gene, and they encode the same protein. [provided by RefSeq, Jul 2008]

WFDC8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130896.3. 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
	WFDC8	NM_130896.3	MANE Select	c.-125G>A		upstream_gene	N/A	NP_570966.2	Q8IUA0
	WFDC8	NM_181510.3		c.-125G>A		upstream_gene	N/A	NP_852611.2	A0A140VK68

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFDC8	ENST00000289953.3	TSL:1 MANE Select	c.-125G>A		upstream_gene	N/A	ENSP00000289953.2	Q8IUA0
	WFDC8	ENST00000357199.8	TSL:1	c.-125G>A		upstream_gene	N/A	ENSP00000361735.3	Q8IUA0

Frequencies

GnomAD3 genomes

AF:

0.335

AC:

50809

AN:

151810

Hom.:

9350

Cov.:

show subpopulations

Gnomad AFR

AF:

0.250

Gnomad AMI

AF:

0.459

Gnomad AMR

AF:

0.271

Gnomad ASJ

AF:

0.274

Gnomad EAS

AF:

0.00387

Gnomad SAS

AF:

0.252

Gnomad FIN

AF:

0.403

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.423

Gnomad OTH

AF:

0.328

GnomAD4 exome

AF:

0.380

AC:

426372

AN:

1123102

Hom.:

87039

Cov.:

AF XY:

0.378

AC XY:

215099

AN XY:

569574

show subpopulations

African (AFR)

AF:

0.242

AC:

6490

AN:

26774

American (AMR)

AF:

0.190

AC:

7546

AN:

39638

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

5709

AN:

21310

East Asian (EAS)

AF:

0.000722

AC:

AN:

37416

South Asian (SAS)

AF:

0.262

AC:

19187

AN:

73280

European-Finnish (FIN)

AF:

0.413

AC:

20941

AN:

50758

Middle Eastern (MID)

AF:

0.335

AC:

1670

AN:

4990

European-Non Finnish (NFE)

AF:

0.424

AC:

347577

AN:

820194

Other (OTH)

AF:

0.353

AC:

17225

AN:

48742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

12162

24324

36487

48649

60811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9092

18184

27276

36368

45460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.334

AC:

50811

AN:

151928

Hom.:

9352

Cov.:

AF XY:

0.330

AC XY:

24460

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.250

AC:

10339

AN:

41436

American (AMR)

AF:

0.270

AC:

4126

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

950

AN:

3470

East Asian (EAS)

AF:

0.00369

AC:

AN:

5156

South Asian (SAS)

AF:

0.255

AC:

1229

AN:

4816

European-Finnish (FIN)

AF:

0.403

AC:

4243

AN:

10526

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.423

AC:

28708

AN:

67934

Other (OTH)

AF:

0.323

AC:

683

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1636

3272

4908

6544

8180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

494

988

1482

1976

2470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.377

Hom.:

1461

Bravo

AF:

0.317

Asia WGS

AF:

0.111

AC:

388

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

6.6

(source)

DANN

Benign

0.62

PhyloP100

-0.31

PromoterAI

-0.0061

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over