Genetic Variant NM_001925.3:c.-158C>G (chr8-6938371-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.-158C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,048 control chromosomes in the GnomAD database, including 2,120 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 0.15 ( 2120 hom., cov: 32)

Exomes 𝑓: 0.16 ( 0 hom. )

Consequence

DEFA4
NM_001925.3 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.761

Publications

1 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=-0.93).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFA4	NM_001925.3 link	c.-158C>G		upstream_gene_variant		ENST00000297435.3	NP_001916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFA4	ENST00000297435.3 link	c.-158C>G		upstream_gene_variant		1	NM_001925.3	ENSP00000297435.2

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22592

AN:

151900

Hom.:

2123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0470

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.215

Gnomad EAS

AF:

0.0974

Gnomad SAS

AF:

0.0780

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.185

GnomAD4 exome

AF:

0.156

AC:

AN:

Hom.:

Cov.:

AF XY:

0.133

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.154

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.149

AC:

22598

AN:

152016

Hom.:

2120

Cov.:

AF XY:

0.145

AC XY:

10770

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.0470

AC:

1949

AN:

41504

American (AMR)

AF:

0.203

AC:

3097

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.215

AC:

746

AN:

3468

East Asian (EAS)

AF:

0.0968

AC:

500

AN:

5164

South Asian (SAS)

AF:

0.0781

AC:

374

AN:

4788

European-Finnish (FIN)

AF:

0.145

AC:

1528

AN:

10556

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.203

AC:

13782

AN:

67966

Other (OTH)

AF:

0.186

AC:

393

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

978

1957

2935

3914

4892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<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:

0.0396

Hom.:

Bravo

AF:

0.152

Asia WGS

AF:

0.0880

AC:

307

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.5

(source)

DANN

Benign

0.55

PhyloP100

0.76

PromoterAI

0.0092

Neutral

(source)

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over