8-6936878-C-G

Position:

• chr8-6936878-C-G

Variant summary

Our verdict is Benign. Variant got -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. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8V) has been classified as Likely benign.

• 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

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 (MetaRNN=0.002696991).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFA4	NM_001925.3	c.22G>C	p.Ala8Pro	missense_variant	2/3	ENST00000297435.3	NP_001916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEFA4	ENST00000297435.3	c.22G>C	p.Ala8Pro	missense_variant	2/3	1	NM_001925.3	ENSP00000297435	P1

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

GnomAD3 exomes AF: 0.0188 AC: 4624 AN: 246604 Hom.: 116 AF XY: 0.0161 AC XY: 2139 AN XY: 133270

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 SAS exome AF: 0.00444

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

Gnomad4 AFR exome AF: 0.0819

Gnomad4 AMR exome AF: 0.0236

Gnomad4 ASJ exome AF: 0.00570

Gnomad4 EAS exome AF: 0.0639

Gnomad4 SAS exome AF: 0.00481

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.00476

Gnomad4 OTH exome AF: 0.0138

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

Gnomad4 AFR AF: 0.0792

Gnomad4 AMR AF: 0.0193

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0568

Gnomad4 SAS AF: 0.00459

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.00515

Gnomad4 OTH AF: 0.0250

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 v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

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