20-45538052-A-C

Variant names:

• chr20-45538052-A-C
• rs138817814
• NM_080827.2:c.134T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080827.2(WFDC6):​c.134T>G​(p.Ile45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I45T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WFDC6 NM_080827.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 0 publications found

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]

ENSG00000237464 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031443298).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080827.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFDC6	NM_080827.2	MANE Select	c.134T>G	p.Ile45Arg	missense	Exon 2 of 3	NP_543017.1	Q9BQY6-2
	EPPIN-WFDC6	NM_001198986.2		c.434T>G	p.Ile145Arg	missense	Exon 4 of 5	NP_001185915.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFDC6	ENST00000372670.8	TSL:1 MANE Select	c.134T>G	p.Ile45Arg	missense	Exon 2 of 3	ENSP00000361755.3	Q9BQY6-2
	EPPIN-WFDC6	ENST00000651288.1		c.434T>G	p.Ile145Arg	missense	Exon 4 of 5	ENSP00000498632.1	A0A494C0M2
	EPPIN-WFDC6	ENST00000504988.1	TSL:2	c.434T>G	p.Ile145Arg	missense	Exon 4 of 5	ENSP00000424176.1	O95925-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.30
DANN	Benign	0.34
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.64	T
PhyloP100		-1.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	4.5	N
REVEL	Benign	0.11
Sift	Benign	0.76	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.34		Gain of solvent accessibility (P = 0.0039)
MVP		0.14
MPC		0.085
ClinPred		0.035	T
GERP RS		-5.8
Varity_R		0.035
gMVP		0.35
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs138817814; hg19: chr20-44166691;