NM_001925.3:c.22G>C

Variant names:

• chr8-6936878-C-G
• rs28661751
• NM_001925.3:c.22G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001925.3(DEFA4):​c.22G>C​(p.Ala8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,608,078 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (135 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (267 hom.)
• Consequence: DEFA4 NM_001925.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 5 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002696991).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001925.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFA4	NM_001925.3	MANE Select	c.22G>C	p.Ala8Pro	missense	Exon 2 of 3	NP_001916.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFA4	ENST00000297435.3	TSL:1 MANE Select	c.22G>C	p.Ala8Pro	missense	Exon 2 of 3	ENSP00000297435.2

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4524 AN: 152030 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.00501

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0188 AC: 4624 AN: 246604 AF XY: 0.0161

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.0252

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.0633

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00601

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.00959 AC: 13968 AN: 1455930 Hom.: 267 Cov.: 31 AF XY: 0.00899 AC XY: 6508 AN XY: 723700

African (AFR) AF: 0.0819 AC: 2729 AN: 33302

American (AMR) AF: 0.0236 AC: 1048 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.00570 AC: 148 AN: 25980

East Asian (EAS) AF: 0.0639 AC: 2523 AN: 39508

South Asian (SAS) AF: 0.00481 AC: 409 AN: 85116

European-Finnish (FIN) AF: 0.0169 AC: 897 AN: 53146

Middle Eastern (MID) AF: 0.0191 AC: 108 AN: 5658

European-Non Finnish (NFE) AF: 0.00476 AC: 5278 AN: 1108770

Other (OTH) AF: 0.0138 AC: 828 AN: 60092

GnomAD4 genome AF: 0.0298 AC: 4533 AN: 152148 Hom.: 135 Cov.: 32 AF XY: 0.0299 AC XY: 2227 AN XY: 74366

African (AFR) AF: 0.0792 AC: 3286 AN: 41502

American (AMR) AF: 0.0193 AC: 295 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.0568 AC: 294 AN: 5174

South Asian (SAS) AF: 0.00459 AC: 22 AN: 4788

European-Finnish (FIN) AF: 0.0191 AC: 202 AN: 10596

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00515 AC: 350 AN: 68002

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.00477 Hom.: 3

Bravo AF: 0.0329

ExAC AF: 0.0196 AC: 2381

Asia WGS AF: 0.0400 AC: 138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.8
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0019	N
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.4
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.093
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.95	P
Vest4		0.21
MPC		0.0012
ClinPred		0.054	T
GERP RS		-1.5
Varity_R		0.73
gMVP		0.10
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28661751; hg19: chr8-6794400; COSMIC: COSV52404929;