20-45538007-C-T

Variant names:

• chr20-45538007-C-T
• rs141960100
• NM_080827.2:c.179G>A

Variant summary

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

The NM_080827.2(WFDC6):​c.179G>A​(p.Cys60Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,614,004 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: WFDC6 NM_080827.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

Genes affected

WFDC6 (HGNC:16164): (WAP four-disulfide core domain 6) 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. Read-through transcription exists between this gene and the upstream SPINLW1 (serine peptidase inhibitor-like, with Kunitz and WAP domains 1) gene. [provided by RefSeq, Nov 2010]

EPPIN-WFDC6 (HGNC:38825): (EPPIN-WFDC6 readthrough) This locus represents naturally occurring read-through transcription between the neighboring SPINLW1 (serine peptidase inhibitor-like, with Kunitz and WAP domains 1) and WFDC6 (WAP four-disulfide core domain 6) genes. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Nov 2010]

ENSG00000291238 (HGNC:):

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 rank	MANE	Protein	UniProt
WFDC6	NM_080827.2	c.179G>A	p.Cys60Tyr	missense_variant	Exon 2 of 3	ENST00000372670.8	NP_543017.1
EPPIN-WFDC6	NM_001198986.2	c.479G>A	p.Cys160Tyr	missense_variant	Exon 4 of 5		NP_001185915.1
LOC107987282	XR_001754641.3	n.153-529C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFDC6	ENST00000372670.8	c.179G>A	p.Cys60Tyr	missense_variant	Exon 2 of 3	1	NM_080827.2	ENSP00000361755.3
EPPIN-WFDC6	ENST00000651288.1	c.479G>A	p.Cys160Tyr	missense_variant	Exon 4 of 5			ENSP00000498632.1
EPPIN-WFDC6	ENST00000504988.1	c.479G>A	p.Cys160Tyr	missense_variant	Exon 4 of 5	2		ENSP00000424176.1
ENSG00000291238	ENST00000372665.4	n.179G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000368

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251302 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135826

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000427 AC: 624 AN: 1461768 Hom.: 1 Cov.: 31 AF XY: 0.000418 AC XY: 304 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000507

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74432

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000440 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000436

EpiControl AF: 0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.479G>A (p.C160Y) alteration is located in exon 4 (coding exon 4) of the EPPIN-WFDC6 gene. This alteration results from a G to A substitution at nucleotide position 479, causing the cysteine (C) at amino acid position 160 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	-0.059	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	16
DANN	Benign	0.68
DEOGEN2	Uncertain	0.64	.;D;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Pathogenic	0.90	D
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.010	D;.;D
Polyphen		0.98	D;.;.
Vest4		0.71
MVP		0.51
MPC		0.17
ClinPred		0.50	T
GERP RS		3.5
Varity_R		0.12
gMVP		0.80

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: rs141960100; hg19: chr20-44166646;