rs28661751

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-6936878-C-A
• chr8-6936878-C-G
• chr8-6936878-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000297435.3(DEFA4):​c.22G>T​(p.Ala8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,608,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: DEFA4 ENST00000297435.3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000297435.3. 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>T	p.Ala8Ser	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>T	p.Ala8Ser	missense	Exon 2 of 3	ENSP00000297435.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246604 AF XY: 0.00000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000350 AC: 51 AN: 1455976 Hom.: 0 Cov.: 31 AF XY: 0.0000318 AC XY: 23 AN XY: 723718

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 85116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.0000433 AC: 48 AN: 1108780

Other (OTH) AF: 0.0000499 AC: 3 AN: 60096

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.4
DANN	Benign	0.71
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0015	N
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.024
Sift	Benign	0.36	T
Sift4G	Benign	0.10	T
Polyphen		0.59	P
Vest4		0.22
MutPred		0.48		Gain of disorder (P = 0.097)
MVP		0.14
MPC		0.0017
ClinPred		0.068	T
GERP RS		-1.5
Varity_R		0.078
gMVP		0.065
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -19

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

Other links and lift over

dbSNP: rs28661751; hg19: chr8-6794400;