rs2239667

Positions:

• chr8-6936685-G-A
• chr8-6936685-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001925.3(DEFA4):​c.172+43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,498,906 control chromosomes in the GnomAD database, including 43,898 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 0.22 (3789 hom., cov: 32)
  • Exomes 𝑓: 0.24 (40109 hom.)
• Consequence: DEFA4 NM_001925.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.36

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFA4	NM_001925.3	c.172+43C>T		intron_variant		ENST00000297435.3	NP_001916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEFA4	ENST00000297435.3	c.172+43C>T		intron_variant		1	NM_001925.3	ENSP00000297435	P1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33210 AN: 151938 Hom.: 3793 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.226 AC: 43206 AN: 190950 Hom.: 5184 AF XY: 0.230 AC XY: 23572 AN XY: 102404

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.307

Gnomad SAS exome AF: 0.229

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.240 AC: 323004 AN: 1346848 Hom.: 40109 Cov.: 29 AF XY: 0.240 AC XY: 158229 AN XY: 659662

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.218 AC: 33202 AN: 152058 Hom.: 3789 Cov.: 32 AF XY: 0.219 AC XY: 16261 AN XY: 74298

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.220

Alfa AF: 0.174 Hom.: 629

Bravo AF: 0.211

Asia WGS AF: 0.269 AC: 938 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	1.2
DANN	Benign	0.41

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

Other links and lift over

dbSNP: rs2239667; hg19: chr8-6794207;