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

Variant summary

Our verdict is Benign. The variant received -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. 13/20 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. V38D) has been classified as Uncertain significance.

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

Publications

21 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005218.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFB1	NM_005218.4	MANE Select	c.112G>A	p.Val38Ile	missense	Exon 2 of 2	NP_005209.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DEFB1	ENST00000297439.4	TSL:1 MANE Select	c.112G>A	p.Val38Ile	missense	Exon 2 of 2	ENSP00000297439.3
GS1-24F4.2	ENST00000531701.2	TSL:3	n.602-14346C>T		intron	N/A
GS1-24F4.2	ENST00000655804.2		n.340-2405C>T		intron	N/A

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

GnomAD2 exomes

AF:

0.0103

AC:

2595

AN:

251436

AF XY:

0.00763

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 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

African (AFR)

AF:

0.121

AC:

4053

AN:

33474

American (AMR)

AF:

0.00725

AC:

324

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0256

AC:

1016

AN:

39700

South Asian (SAS)

AF:

0.00123

AC:

106

AN:

86256

European-Finnish (FIN)

AF:

0.000393

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000517

AC:

575

AN:

1112006

Other (OTH)

AF:

0.00841

AC:

508

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

311

621

932

1242

1553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0359

AC:

5464

AN:

152272

Hom.:

316

Cov.:

AF XY:

0.0352

AC XY:

2621

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.125

AC:

5182

AN:

41518

American (AMR)

AF:

0.00974

AC:

149

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00887

AC:

AN:

5186

South Asian (SAS)

AF:

0.00269

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68036

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

236

472

707

943

1179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0105

Hom.:

163

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.2

(source)

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

PhyloP100

0.090

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

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over