Genetic Variant DEFB113:p.Val58Ile (chr6-49968754-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001037729.1(DEFB113):c.172G>A(p.Val58Ile) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DEFB113
NM_001037729.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.451

Variant links:

Genes affected

DEFB113 (HGNC:18094): (defensin beta 113) Defensins form a family of antimicrobial and cytotoxic peptides made by neutrophils. Defensins are short, processed peptide molecules that are classified by structure into three groups: alpha-defensins, beta-defensins and theta-defensins. All beta-defensin genes are densely clustered in four to five syntenic chromosomal regions. [provided by RefSeq, Oct 2014]

DEFB113 links:

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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=0.058923006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB113	NM_001037729.1 link	c.172G>A	p.Val58Ile	missense_variant	Exon 2 of 2	ENST00000398718.1	NP_001032818.1	Q30KQ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFB113	ENST00000398718.1 link	c.172G>A	p.Val58Ile	missense_variant	Exon 2 of 2	1	NM_001037729.1	ENSP00000381703.1		Q30KQ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000436

AC:

AN:

229362

Hom.:

AF XY:

0.00

AC XY:

AN XY:

124618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000600

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442462

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716696

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172G>A (p.V58I) alteration is located in exon 2 (coding exon 2) of the DEFB113 gene. This alteration results from a G to A substitution at nucleotide position 172, causing the valine (V) at amino acid position 58 to be replaced by an isoleucine (I). 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

Benign

0.079

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.061

DANN

Benign

0.91

DEOGEN2

Benign

0.034

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.34

M_CAP

Benign

0.0014

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.54

REVEL

Benign

0.0090

Sift

Benign

0.53

Sift4G

Benign

0.36

Polyphen

0.0090

Vest4

0.074

MutPred

0.27

Loss of catalytic residue at V58 (P = 0.0464);

MVP

0.048

MPC

0.0031

ClinPred

0.015

GERP RS

-6.9

Varity_R

0.016

gMVP

0.14

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