20-45579234-C-T

Variant summary

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

The NM_130896.3(WFDC8):​c.14G>A​(p.Arg5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

WFDC8
NM_130896.3 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.34
Variant links:
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]

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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=0.081968755).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WFDC8NM_130896.3 linkc.14G>A p.Arg5Gln missense_variant Exon 1 of 6 ENST00000289953.3 NP_570966.2 Q8IUA0A0A140VK68
WFDC8NM_181510.3 linkc.14G>A p.Arg5Gln missense_variant Exon 1 of 7 NP_852611.2 Q8IUA0A0A140VK68
WFDC8XM_017028119.2 linkc.14G>A p.Arg5Gln missense_variant Exon 1 of 5 XP_016883608.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WFDC8ENST00000289953.3 linkc.14G>A p.Arg5Gln missense_variant Exon 1 of 6 1 NM_130896.3 ENSP00000289953.2 Q8IUA0
WFDC8ENST00000357199.8 linkc.14G>A p.Arg5Gln missense_variant Exon 1 of 7 1 ENSP00000361735.3 Q8IUA0

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251394
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461832
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
4.8
DANN
Benign
0.51
DEOGEN2
Benign
0.0022
T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.0016
N
LIST_S2
Benign
0.56
.;T
M_CAP
Benign
0.0070
T
MetaRNN
Benign
0.082
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.30
N;N
REVEL
Benign
0.024
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.40
T;T
Polyphen
0.80
P;P
Vest4
0.043
MutPred
0.34
Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP
0.17
MPC
0.14
ClinPred
0.047
T
GERP RS
-0.29
Varity_R
0.042
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs373025670; hg19: chr20-44207873; COSMIC: COSV51488520; API