20-45704921-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000335769.2(WFDC10B):​c.71G>A​(p.Cys24Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,942 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000089 ( 3 hom. )

Consequence

WFDC10B
ENST00000335769.2 missense

Scores

2
1
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0500
Variant links:
Genes affected
WFDC10B (HGNC:20479): (WAP four-disulfide core domain 10B) 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. Two alternatively spliced transcript variants have been found for this gene, and they encode distinct isoforms. [provided by RefSeq, Jul 2008]
WFDC13 (HGNC:16131): (WAP four-disulfide core domain 13) 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1349473).
BS2
High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WFDC10BNM_172006.2 linkuse as main transcriptc.-133G>A 5_prime_UTR_variant 1/4 ENST00000330523.10
WFDC13NM_172005.2 linkuse as main transcriptc.239+327C>T intron_variant ENST00000305479.3
WFDC10BNM_172131.2 linkuse as main transcriptc.71G>A p.Cys24Tyr missense_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WFDC10BENST00000335769.2 linkuse as main transcriptc.71G>A p.Cys24Tyr missense_variant 1/31 Q8IUB3-2
WFDC10BENST00000330523.10 linkuse as main transcriptc.-133G>A 5_prime_UTR_variant 1/41 NM_172006.2 P1Q8IUB3-1
WFDC13ENST00000305479.3 linkuse as main transcriptc.239+327C>T intron_variant 1 NM_172005.2 P1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152152
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
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:
0.00
Gnomad OTH
AF:
0.000479
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461790
Hom.:
3
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152152
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000720
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingAmbry GeneticsMar 24, 2023The c.71G>A (p.C24Y) alteration is located in exon 1 (coding exon 1) of the WFDC10B gene. This alteration results from a G to A substitution at nucleotide position 71, causing the cysteine (C) at amino acid position 24 to be replaced by a tyrosine (Y). 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
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
1.6
DANN
Benign
0.72
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.39
T
M_CAP
Benign
0.0028
T
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PROVEAN
Uncertain
-3.0
D
REVEL
Benign
0.035
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.98
D
Vest4
0.21
MutPred
0.28
Gain of sheet (P = 0.0477);
MVP
0.18
MPC
0.095
ClinPred
0.24
T
GERP RS
-0.34
gMVP
0.11

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.

Other links and lift over

dbSNP: rs761638791; hg19: chr20-44333560; API