Genetic Variant NM_005218.4:c.112G>A (chr8-6870776-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005218.4(DEFB1):c.112G>A(p.Val38Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 1,614,142 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.036 ( 316 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 275 hom. )

Consequence

DEFB1
NM_005218.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0900

Variant links:

Genes affected

DEFB1 (HGNC:2766): (defensin beta 1) Defensins form a family of microbicidal and cytotoxic peptides made by neutrophils. Members of the defensin family are highly similar in protein sequence. This gene encodes defensin, beta 1, an antimicrobial peptide implicated in the resistance of epithelial surfaces to microbial colonization. This gene maps in close proximity to defensin family member, defensin, alpha 1 and has been implicated in the pathogenesis of cystic fibrosis. [provided by RefSeq, Jul 2008]

DEFB1 links:

GS1-24F4.2 (HGNC:):

GS1-24F4.2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026759207).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB1	NM_005218.4 link	c.112G>A	p.Val38Ile	missense_variant	Exon 2 of 2	ENST00000297439.4	NP_005209.1	P60022

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DEFB1	ENST00000297439.4 link	c.112G>A	p.Val38Ile	missense_variant	Exon 2 of 2	1	NM_005218.4	ENSP00000297439.3	P60022
GS1-24F4.2	ENST00000531701.1 link	n.226-14346C>T		intron_variant	Intron 2 of 2	3
GS1-24F4.2	ENST00000655804.1 link	n.323-2405C>T		intron_variant	Intron 2 of 2
GS1-24F4.2	ENST00000657010.1 link	n.*138C>T		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0358

AC:

5447

AN:

152154

Hom.:

314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00975

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00904

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.0103

AC:

2595

AN:

251436

Hom.:

140

AF XY:

0.00763

AC XY:

1037

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.00656

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00930

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00454

AC:

6637

AN:

1461870

Hom.:

275

Cov.:

AF XY:

0.00400

AC XY:

2912

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.121

Gnomad4 AMR exome

AF:

0.00725

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0256

Gnomad4 SAS exome

AF:

0.00123

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.000517

Gnomad4 OTH exome

AF:

0.00841

GnomAD4 genome

AF:

0.0359

AC:

5464

AN:

152272

Hom.:

316

Cov.:

AF XY:

0.0352

AC XY:

2621

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.00974

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00887

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.00326

Hom.:

Bravo

AF:

0.0405

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.124

AC:

545

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0127

AC:

1544

EpiCase

AF:

0.000491

EpiControl

AF:

0.00124

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.2

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.013

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.45

REVEL

Benign

0.049

Sift

Benign

0.17

Sift4G

Benign

0.45

Polyphen

0.93

Vest4

0.053

MPC

0.00028

ClinPred

0.013

GERP RS

2.2

Varity_R

0.15

gMVP

0.091

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over