20-45704450-T-A

Position:

• chr20-45704450-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_172005.2(WFDC13):​c.95T>A​(p.Ile32Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: WFDC13 NM_172005.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC13	NM_172005.2	c.95T>A	p.Ile32Asn	missense_variant	2/4	ENST00000305479.3	NP_742002.1
WFDC10B	NM_172006.2	c.-65+47A>T		intron_variant		ENST00000330523.10	NP_742003.1
WFDC10B	NM_172131.2	c.139+47A>T		intron_variant			NP_742143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFDC13	ENST00000305479.3	c.95T>A	p.Ile32Asn	missense_variant	2/4	1	NM_172005.2	ENSP00000302938.2
WFDC10B	ENST00000330523.10	c.-65+47A>T		intron_variant		1	NM_172006.2	ENSP00000327628.5
WFDC10B	ENST00000335769.2	c.139+47A>T		intron_variant		1		ENSP00000337466.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.95T>A (p.I32N) alteration is located in exon 2 (coding exon 2) of the WFDC13 gene. This alteration results from a T to A substitution at nucleotide position 95, causing the isoleucine (I) at amino acid position 32 to be replaced by an asparagine (N). 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	0.63
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.47	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.39		Gain of loop (P = 0.0013);
MVP		0.30
MPC		0.31
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.67
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44333089;