dbSNP rs2741680: DEFA4:c.172+136C>G (chr8-6936592-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001925.3(DEFA4):c.172+136C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 805,574 control chromosomes in the GnomAD database, including 14,261 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 0.14 ( 2012 hom., cov: 33)

Exomes 𝑓: 0.18 ( 12249 hom. )

Consequence

DEFA4
NM_001925.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.49

Publications

2 publications found

Variant links:

Genes affected

DEFA4 (HGNC:2763): (defensin alpha 4) Defensins are a family of antimicrobial and cytotoxic peptides thought to be involved in host defense. They are abundant in the granules of neutrophils and also found in the epithelia of mucosal surfaces such as those of the intestine, respiratory tract, urinary tract, and vagina. Members of the defensin family are highly similar in protein sequence and distinguished by a conserved cysteine motif. Several alpha defensin genes are clustered on chromosome 8. This gene differs from other genes of this family by an extra 83-base segment that is apparently the result of a recent duplication within the coding region. The protein encoded by this gene, defensin, alpha 4, is found in the neutrophils; it exhibits corticostatic activity and inhibits corticotropin stimulated corticosterone production. [provided by RefSeq, Oct 2014]

DEFA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFA4	NM_001925.3 link	c.172+136C>G		intron_variant	Intron 2 of 2	ENST00000297435.3	NP_001916.1	P12838

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFA4	ENST00000297435.3 link	c.172+136C>G		intron_variant	Intron 2 of 2	1	NM_001925.3	ENSP00000297435.2		P12838

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22036

AN:

151992

Hom.:

2014

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0438

Gnomad AMI

AF:

0.179

Gnomad AMR

AF:

0.201

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.0972

Gnomad SAS

AF:

0.0785

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.183

GnomAD4 exome

AF:

0.184

AC:

119942

AN:

653464

Hom.:

12249

AF XY:

0.182

AC XY:

59845

AN XY:

329362

show subpopulations

African (AFR)

AF:

0.0427

AC:

668

AN:

15650

American (AMR)

AF:

0.196

AC:

2909

AN:

14864

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

2610

AN:

13570

East Asian (EAS)

AF:

0.111

AC:

3360

AN:

30172

South Asian (SAS)

AF:

0.0742

AC:

2456

AN:

33096

European-Finnish (FIN)

AF:

0.141

AC:

4853

AN:

34304

Middle Eastern (MID)

AF:

0.184

AC:

654

AN:

3548

European-Non Finnish (NFE)

AF:

0.203

AC:

96840

AN:

476538

Other (OTH)

AF:

0.176

AC:

5592

AN:

31722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

4742

9483

14225

18966

23708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2640

5280

7920

10560

13200

<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:

0.145

AC:

22043

AN:

152110

Hom.:

2012

Cov.:

AF XY:

0.142

AC XY:

10554

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0437

AC:

1814

AN:

41536

American (AMR)

AF:

0.201

AC:

3076

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

740

AN:

3468

East Asian (EAS)

AF:

0.0966

AC:

500

AN:

5174

South Asian (SAS)

AF:

0.0785

AC:

376

AN:

4788

European-Finnish (FIN)

AF:

0.144

AC:

1529

AN:

10588

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.197

AC:

13389

AN:

67966

Other (OTH)

AF:

0.185

AC:

392

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

939

1878

2818

3757

4696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<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:

0.0388

Hom.:

Bravo

AF:

0.149

Asia WGS

AF:

0.0920

AC:

322

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.13

(source)

DANN

Benign

0.38

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over