Variant 20-45110421-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_145652.4(WFDC5):c.346G>C(p.Asp116His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,116 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: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

WFDC5
NM_145652.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37

Variant links:

Genes affected

WFDC5 (HGNC:20477): (WAP four-disulfide core domain 5) This gene encodes a member of the WAP-type four-disulfide core (WFDC) domain family. Most WFDC proteins contain only one WFDC domain, and this encoded protein contains two WFDC domains. 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 centromeric cluster. [provided by RefSeq, Jul 2008]

WFDC5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35271907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC5	NM_145652.4 linkuse as main transcript	c.346G>C	p.Asp116His	missense_variant	3/4	ENST00000372789.6	NP_663627.1	Q8TCV5-2
WFDC5	NM_001395506.1 linkuse as main transcript	c.346G>C	p.Asp116His	missense_variant	5/6		NP_001382435.1
WFDC5	XM_047439930.1 linkuse as main transcript	c.352G>C	p.Asp118His	missense_variant	2/3		XP_047295886.1
WFDC5	XM_011528601.2 linkuse as main transcript	c.346G>C	p.Asp116His	missense_variant	4/5		XP_011526903.1	Q8TCV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC5	ENST00000372789.6 linkuse as main transcript	c.346G>C	p.Asp116His	missense_variant	3/4	1	NM_145652.4	ENSP00000361875.4		Q8TCV5-2
WFDC5	ENST00000307971.7 linkuse as main transcript	c.346G>C	p.Asp116His	missense_variant	3/4	5		ENSP00000312381.4		Q8TCV5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000126

AC:

AN:

237418

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

128632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000170

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456116

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723818

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Feb 22, 2024

The c.346G>C (p.D116H) alteration is located in exon 3 (coding exon 3) of the WFDC5 gene. This alteration results from a G to C substitution at nucleotide position 346, causing the aspartic acid (D) at amino acid position 116 to be replaced by a histidine (H). 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

Pathogenic

0.90

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.35

T;T

MetaSVM

Uncertain

0.062

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.059

T;T

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.36

MutPred

0.34

Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);

MVP

0.45

MPC

0.71

ClinPred

0.80

GERP RS

5.1

Varity_R

0.27

gMVP

0.65

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