20-45538052-A-G

Position:

chr20-45538052-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080827.2(WFDC6):c.134T>C(p.Ile45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

WFDC6
NM_080827.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.42

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 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=0.0074533224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFDC6	NM_080827.2 linkuse as main transcript	c.134T>C	p.Ile45Thr	missense_variant	2/3	ENST00000372670.8	NP_543017.1	Q9BQY6-2A0A0K0K1K0
EPPIN-WFDC6	NM_001198986.2 linkuse as main transcript	c.434T>C	p.Ile145Thr	missense_variant	4/5		NP_001185915.1	O95925-3
LOC107987282	XR_001754641.3 linkuse as main transcript	n.153-484A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
WFDC6	ENST00000372670.8 linkuse as main transcript	c.134T>C	p.Ile45Thr	missense_variant	2/3	1	NM_080827.2	ENSP00000361755.3	Q9BQY6-2
EPPIN-WFDC6	ENST00000651288.1 linkuse as main transcript	c.434T>C	p.Ile145Thr	missense_variant	4/5			ENSP00000498632.1	A0A494C0M2
EPPIN-WFDC6	ENST00000504988.1 linkuse as main transcript	c.434T>C	p.Ile145Thr	missense_variant	4/5	2		ENSP00000424176.1	O95925-3
ENSG00000291238	ENST00000372665.4 linkuse as main transcript	n.134T>C		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251260

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000335

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000348

Hom.:

Bravo

AF:

0.000385

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Jul 28, 2021

The c.434T>C (p.I145T) alteration is located in exon 4 (coding exon 4) of the EPPIN-WFDC6 gene. This alteration results from a T to C substitution at nucleotide position 434, causing the isoleucine (I) at amino acid position 145 to be replaced by a threonine (T). 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

-0.50

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.35

DANN

Benign

0.36

DEOGEN2

Benign

0.12

.;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.24

T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-0.68

PrimateAI

Benign

0.38

PROVEAN

Benign

0.87

N;N;N

REVEL

Benign

0.039

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.28

T;.;T

Polyphen

0.0

B;.;.

Vest4

0.17

MVP

0.20

MPC

0.22

ClinPred

0.0022

GERP RS

-5.8

Varity_R

0.019

gMVP

0.28

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