20-45538007-C-T

Position:

chr20-45538007-C-T

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Variant links:

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]

WFDC6 links:

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]

EPPIN-WFDC6 links:

ENSG00000291238 (HGNC:):

ENSG00000291238 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
WFDC6	NM_080827.2 link	c.179G>A	p.Cys60Tyr	missense_variant	2/3	ENST00000372670.8	NP_543017.1	Q9BQY6-2A0A0K0K1K0
EPPIN-WFDC6	NM_001198986.2 link	c.479G>A	p.Cys160Tyr	missense_variant	4/5		NP_001185915.1	O95925-3
LOC107987282	XR_001754641.3 link	n.153-529C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
WFDC6	ENST00000372670.8 link	c.179G>A	p.Cys60Tyr	missense_variant	2/3	1	NM_080827.2	ENSP00000361755.3	Q9BQY6-2
EPPIN-WFDC6	ENST00000651288.1 link	c.479G>A	p.Cys160Tyr	missense_variant	4/5			ENSP00000498632.1	A0A494C0M2
EPPIN-WFDC6	ENST00000504988.1 link	c.479G>A	p.Cys160Tyr	missense_variant	4/5	2		ENSP00000424176.1	O95925-3
ENSG00000291238	ENST00000372665.4 link	n.179G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

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:

AN:

251302

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135826

show subpopulations

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.:

Cov.:

AF XY:

0.000418

AC XY:

304

AN XY:

727182

show subpopulations

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:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74432

show subpopulations

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.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2022

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

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Uncertain

0.64

.;D;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.54

T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Pathogenic

0.90

PrimateAI

Benign

0.31

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over