Genetic Variant NM_001205266.2:c.*127G>A (chr8-7414834-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001205266.2(DEFB4B):c.*127G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0476 in 147,436 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.048 ( 15 hom., cov: 45)

Exomes 𝑓: 0.055 ( 120 hom. )

Failed GnomAD Quality Control

Consequence

DEFB4B
NM_001205266.2 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.475

Publications

1 publications found

Variant links:

COSMIC-nc: COSV58939950

Genes affected

DEFB4B (HGNC:30193): (defensin beta 4B) 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 4, an antibiotic peptide which is locally regulated by inflammation. [provided by RefSeq, Oct 2014]

DEFB4B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB4B	NM_001205266.2 link	c.*127G>A		downstream_gene_variant		ENST00000318157.3	NP_001192195.1	O15263

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFB4B	ENST00000318157.3 link	c.*127G>A		downstream_gene_variant		1	NM_001205266.2	ENSP00000424598.1		O15263

Frequencies

GnomAD3 genomes

AF:

0.0476

AC:

7009

AN:

147316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.0436

Gnomad AMR

AF:

0.0877

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.137

Gnomad SAS

AF:

0.0324

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.0588

Gnomad NFE

AF:

0.0567

Gnomad OTH

AF:

0.0543

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0549

AC:

76184

AN:

1388402

Hom.:

120

Cov.:

AF XY:

0.0543

AC XY:

37513

AN XY:

691026

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0106

AC:

346

AN:

32554

American (AMR)

AF:

0.0688

AC:

2835

AN:

41228

Ashkenazi Jewish (ASJ)

AF:

0.0412

AC:

1025

AN:

24870

East Asian (EAS)

AF:

0.143

AC:

5201

AN:

36456

South Asian (SAS)

AF:

0.0335

AC:

2772

AN:

82840

European-Finnish (FIN)

AF:

0.0352

AC:

1819

AN:

51628

Middle Eastern (MID)

AF:

0.0595

AC:

308

AN:

5180

European-Non Finnish (NFE)

AF:

0.0555

AC:

58665

AN:

1056404

Other (OTH)

AF:

0.0561

AC:

3213

AN:

57242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.305

Heterozygous variant carriers

5650

11300

16950

22600

28250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2310

4620

6930

9240

11550

<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:

0.0476

AC:

7011

AN:

147436

Hom.:

Cov.:

AF XY:

0.0488

AC XY:

3516

AN XY:

72110

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0122

AC:

501

AN:

41108

American (AMR)

AF:

0.0876

AC:

1281

AN:

14618

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

155

AN:

3344

East Asian (EAS)

AF:

0.138

AC:

661

AN:

4798

South Asian (SAS)

AF:

0.0322

AC:

152

AN:

4720

European-Finnish (FIN)

AF:

0.0377

AC:

390

AN:

10344

Middle Eastern (MID)

AF:

0.0559

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0567

AC:

3705

AN:

65302

Other (OTH)

AF:

0.0548

AC:

112

AN:

2044

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.311

Heterozygous variant carriers

487

974

1462

1949

2436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0593

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

2.3

(source)

DANN

Benign

0.62

PhyloP100

-0.47

Mutation Taster

=93/7

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over