8-6936592-G-T

Variant names:

• chr8-6936592-G-T
• rs2741680
• NM_001925.3:c.172+136C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001925.3(DEFA4):​c.172+136C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 654,594 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: DEFA4 NM_001925.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFA4	NM_001925.3	c.172+136C>A		intron_variant	Intron 2 of 2	ENST00000297435.3	NP_001916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFA4	ENST00000297435.3	c.172+136C>A		intron_variant	Intron 2 of 2	1	NM_001925.3	ENSP00000297435.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000153 AC: 1 AN: 654594 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 329958

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15654

American (AMR) AF: 0.00 AC: 0 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13588

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 33140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3558

European-Non Finnish (NFE) AF: 0.00000209 AC: 1 AN: 477454

Other (OTH) AF: 0.00 AC: 0 AN: 31772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 30

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.33
PhyloP100		-1.5

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: rs2741680; hg19: chr8-6794114;