8-6936018-C-T

Variant names:

• chr8-6936018-C-T
• rs736227
• NM_001925.3:c.*2G>A

Variant summary

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

The NM_001925.3(DEFA4):​c.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,613,382 control chromosomes in the GnomAD database, including 362,715 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 0.67 (34137 hom., cov: 32)
  • Exomes 𝑓: 0.67 (328578 hom.)
• Consequence: DEFA4 NM_001925.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.73
• Publications: 21 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]

ENSG00000295941 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFA4	NM_001925.3	c.*2G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000297435.3	NP_001916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFA4	ENST00000297435.3	c.*2G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_001925.3	ENSP00000297435.2
ENSG00000295941	ENST00000734230.1	n.134C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101253 AN: 151856 Hom.: 34119 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.685

GnomAD2 exomes AF: 0.633 AC: 159025 AN: 251302 AF XY: 0.637

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.714

Gnomad EAS exome AF: 0.617

Gnomad FIN exome AF: 0.616

Gnomad NFE exome AF: 0.666

Gnomad OTH exome AF: 0.661

GnomAD4 exome AF: 0.668 AC: 976061 AN: 1461410 Hom.: 328578 Cov.: 54 AF XY: 0.667 AC XY: 484698 AN XY: 726992

African (AFR) AF: 0.718 AC: 24021 AN: 33468

American (AMR) AF: 0.493 AC: 22030 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 18761 AN: 26132

East Asian (EAS) AF: 0.600 AC: 23820 AN: 39684

South Asian (SAS) AF: 0.626 AC: 53969 AN: 86152

European-Finnish (FIN) AF: 0.616 AC: 32852 AN: 53358

Middle Eastern (MID) AF: 0.692 AC: 3991 AN: 5768

European-Non Finnish (NFE) AF: 0.680 AC: 756169 AN: 1111758

Other (OTH) AF: 0.670 AC: 40448 AN: 60374

GnomAD4 genome AF: 0.667 AC: 101322 AN: 151972 Hom.: 34137 Cov.: 32 AF XY: 0.660 AC XY: 49017 AN XY: 74254

African (AFR) AF: 0.711 AC: 29468 AN: 41470

American (AMR) AF: 0.581 AC: 8864 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2520 AN: 3468

East Asian (EAS) AF: 0.617 AC: 3188 AN: 5170

South Asian (SAS) AF: 0.634 AC: 3037 AN: 4790

European-Finnish (FIN) AF: 0.616 AC: 6489 AN: 10538

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45340 AN: 67972

Other (OTH) AF: 0.691 AC: 1457 AN: 2110

Alfa AF: 0.666 Hom.: 150666

Bravo AF: 0.667

Asia WGS AF: 0.640 AC: 2229 AN: 3478

EpiCase AF: 0.680

EpiControl AF: 0.678

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs736227; hg19: chr8-6793540; COSMIC: COSV52404826;