rs2741680

Positions:

• chr8-6936592-G-C
• chr8-6936592-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+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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49

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=-1.03).
• 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/exons	MANE	Protein	UniProt
DEFA4	NM_001925.3	c.172+136C>G		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+136C>G		intron_variant		1	NM_001925.3	ENSP00000297435	P1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22036 AN: 151992 Hom.: 2014 Cov.: 33

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

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.0742

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.145 AC: 22043 AN: 152110 Hom.: 2012 Cov.: 33 AF XY: 0.142 AC XY: 10554 AN XY: 74350

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.0966

Gnomad4 SAS AF: 0.0785

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.185

Alfa AF: 0.0388 Hom.: 30

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
DANN	Benign	0.38

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

LitVar

Other links and lift over

dbSNP: rs2741680; hg19: chr8-6794114;