chr20-45702203-G-A

Position:

• chr20-45702203-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172005.2(WFDC13):​c.80G>A​(p.Arg27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,611,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: WFDC13 NM_172005.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.550

Genes affected

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037800968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC13	NM_172005.2	c.80G>A	p.Arg27His	missense_variant	1/4	ENST00000305479.3	NP_742002.1
WFDC10B	NM_172006.2	c.-65+2294C>T		intron_variant		ENST00000330523.10	NP_742003.1
WFDC10B	NM_172131.2	c.139+2294C>T		intron_variant			NP_742143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC13	ENST00000305479.3	c.80G>A	p.Arg27His	missense_variant	1/4	1	NM_172005.2	ENSP00000302938.2
WFDC10B	ENST00000330523.10	c.-65+2294C>T		intron_variant		1	NM_172006.2	ENSP00000327628.5
WFDC10B	ENST00000335769.2	c.139+2294C>T		intron_variant		1		ENSP00000337466.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000126 AC: 31 AN: 246410 Hom.: 0 AF XY: 0.000180 AC XY: 24 AN XY: 133032

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000303

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1459724 Hom.: 0 Cov.: 30 AF XY: 0.000132 AC XY: 96 AN XY: 725860

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000292

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74316

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.011
Sift	Benign	0.30	T
Sift4G	Benign	0.93	T
Polyphen		0.0040	B
Vest4		0.048
MVP		0.12
MPC		0.044
ClinPred		0.027	T
GERP RS		-6.0
Varity_R		0.021
gMVP		0.39

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

Other links and lift over

dbSNP: rs199777220; hg19: chr20-44330842;