NM_130896.3:c.287T>C

Variant names:

• chr20-45555859-A-G
• rs2272955
• NM_130896.3:c.287T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130896.3(WFDC8):​c.287T>C​(p.Met96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,706 control chromosomes in the GnomAD database, including 3,979 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.089 (749 hom., cov: 32)
  • Exomes 𝑓: 0.058 (3230 hom.)
• Consequence: WFDC8 NM_130896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240
• Publications: 14 publications found

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]

ENSG00000237464 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056994855).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFDC8	NM_130896.3	c.287T>C	p.Met96Thr	missense_variant	Exon 4 of 6	ENST00000289953.3	NP_570966.2
WFDC8	NM_181510.3	c.287T>C	p.Met96Thr	missense_variant	Exon 4 of 7		NP_852611.2
WFDC8	XM_017028119.2	c.287T>C	p.Met96Thr	missense_variant	Exon 4 of 5		XP_016883608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFDC8	ENST00000289953.3	c.287T>C	p.Met96Thr	missense_variant	Exon 4 of 6	1	NM_130896.3	ENSP00000289953.2
WFDC8	ENST00000357199.8	c.287T>C	p.Met96Thr	missense_variant	Exon 4 of 7	1		ENSP00000361735.3
ENSG00000237464	ENST00000803561.1	n.520-496A>G		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 13482 AN: 152062 Hom.: 749 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.0685

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.0369

Gnomad FIN AF: 0.0537

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0899

GnomAD2 exomes AF: 0.0701 AC: 17601 AN: 251050 AF XY: 0.0681

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.0434

Gnomad ASJ exome AF: 0.0761

Gnomad EAS exome AF: 0.199

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0581

Gnomad OTH exome AF: 0.0654

GnomAD4 exome AF: 0.0582 AC: 85036 AN: 1461526 Hom.: 3230 Cov.: 33 AF XY: 0.0575 AC XY: 41841 AN XY: 727088

African (AFR) AF: 0.163 AC: 5441 AN: 33464

American (AMR) AF: 0.0444 AC: 1986 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 1890 AN: 26132

East Asian (EAS) AF: 0.176 AC: 6977 AN: 39694

South Asian (SAS) AF: 0.0328 AC: 2831 AN: 86250

European-Finnish (FIN) AF: 0.0507 AC: 2708 AN: 53412

Middle Eastern (MID) AF: 0.0782 AC: 449 AN: 5742

European-Non Finnish (NFE) AF: 0.0528 AC: 58696 AN: 1111742

Other (OTH) AF: 0.0672 AC: 4058 AN: 60374

GnomAD4 genome AF: 0.0887 AC: 13495 AN: 152180 Hom.: 749 Cov.: 32 AF XY: 0.0878 AC XY: 6533 AN XY: 74408

African (AFR) AF: 0.157 AC: 6511 AN: 41482

American (AMR) AF: 0.0643 AC: 982 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 238 AN: 3472

East Asian (EAS) AF: 0.178 AC: 924 AN: 5178

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4824

European-Finnish (FIN) AF: 0.0537 AC: 570 AN: 10606

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0562 AC: 3820 AN: 68024

Other (OTH) AF: 0.0894 AC: 189 AN: 2114

Alfa AF: 0.0668 Hom.: 1997

Bravo AF: 0.0952

TwinsUK AF: 0.0494 AC: 183

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.162 AC: 715

ESP6500EA AF: 0.0590 AC: 507

ExAC AF: 0.0735 AC: 8926

Asia WGS AF: 0.0880 AC: 305 AN: 3478

EpiCase AF: 0.0624

EpiControl AF: 0.0626

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.83
DANN	Benign	0.28
DEOGEN2	Benign	0.0017	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.21	.;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.21	N;N
PhyloP100		-0.24
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.030
Sift	Benign	0.49	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.0010	B;B
Vest4		0.082
MPC		0.15
ClinPred		0.0014	T
GERP RS		-3.8
Varity_R		0.046
gMVP		0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2272955; hg19: chr20-44184498; COSMIC: COSV51488941; COSMIC: COSV51488941;