20-45630895-A-C

Position:

chr20-45630895-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_080753.3(WFDC10A):c.117A>C(p.Lys39Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000448 in 1,605,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

WFDC10A
NM_080753.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.29

Variant links:

Genes affected

WFDC10A (HGNC:16139): (WAP four-disulfide core domain 10A) 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. Most WFDC gene members are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the telomeric cluster. [provided by RefSeq, Jul 2008]

WFDC10A links:

WFDC9 (HGNC:20380): (WAP four-disulfide core domain 9) The WAP-type four-disulfide core (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 in many members of the WFDC domain family. This gene encodes a protein which contains a WFDC domain, and is thus a member of the WFDC domain family. This gene and several other gene family members are clustered at 20q13.12. [provided by RefSeq, Jul 2008]

WFDC9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18344498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC10A	NM_080753.3 linkuse as main transcript	c.117A>C	p.Lys39Asn	missense_variant	2/2	ENST00000372643.4	NP_542791.1	Q9H1F0
WFDC9	NM_147198.4 linkuse as main transcript	c.-153+308T>G		intron_variant		ENST00000326000.2	NP_671731.1	Q8NEX5
WFDC10A	XM_017027679.2 linkuse as main transcript	c.99A>C	p.Lys33Asn	missense_variant	2/2		XP_016883168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC10A	ENST00000372643.4 linkuse as main transcript	c.117A>C	p.Lys39Asn	missense_variant	2/2	1	NM_080753.3	ENSP00000361726.3		Q9H1F0
WFDC9	ENST00000326000.2 linkuse as main transcript	c.-153+308T>G		intron_variant		1	NM_147198.4	ENSP00000320532.1		Q8NEX5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

242618

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000542

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000468

AC:

AN:

1453632

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

723228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000550

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.117A>C (p.K39N) alteration is located in exon 2 (coding exon 2) of the WFDC10A gene. This alteration results from a A to C substitution at nucleotide position 117, causing the lysine (K) at amino acid position 39 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.39

M_CAP

Benign

0.0039

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.027

Sift

Uncertain

0.0050

Sift4G

Benign

0.082

Polyphen

1.0

Vest4

0.16

MutPred

0.58

Loss of methylation at K39 (P = 0.0037);

MVP

0.014

MPC

0.14

ClinPred

0.26

GERP RS

0.38

Varity_R

0.14

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over