8-6936059-A-G

Variant names:

• chr8-6936059-A-G
• rs2738100
• NM_001925.3:c.255T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001925.3(DEFA4):​c.255T>C​(p.Gly85Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,472 control chromosomes in the GnomAD database, including 130,446 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 0.43 (14663 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115783 hom.)
• Consequence: DEFA4 NM_001925.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 19 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.117 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.547 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.255T>C	p.Gly85Gly	synonymous	Exon 3 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.255T>C	p.Gly85Gly	synonymous	Exon 3 of 3	ENSP00000297435.2
	ENSG00000295941	ENST00000734230.1		n.175A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64823 AN: 151890 Hom.: 14652 Cov.: 33

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.406

GnomAD2 exomes AF: 0.389 AC: 97718 AN: 251324 AF XY: 0.397

Gnomad AFR exome AF: 0.555

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.464

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.374

GnomAD4 exome AF: 0.392 AC: 573591 AN: 1461466 Hom.: 115783 Cov.: 46 AF XY: 0.395 AC XY: 286992 AN XY: 727014

African (AFR) AF: 0.561 AC: 18794 AN: 33472

American (AMR) AF: 0.231 AC: 10321 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8947 AN: 26134

East Asian (EAS) AF: 0.429 AC: 17024 AN: 39700

South Asian (SAS) AF: 0.483 AC: 41632 AN: 86164

European-Finnish (FIN) AF: 0.404 AC: 21551 AN: 53376

Middle Eastern (MID) AF: 0.381 AC: 2193 AN: 5762

European-Non Finnish (NFE) AF: 0.386 AC: 429057 AN: 1111772

Other (OTH) AF: 0.399 AC: 24072 AN: 60364

GnomAD4 genome AF: 0.427 AC: 64880 AN: 152006 Hom.: 14663 Cov.: 33 AF XY: 0.424 AC XY: 31506 AN XY: 74294

African (AFR) AF: 0.553 AC: 22926 AN: 41460

American (AMR) AF: 0.288 AC: 4404 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3470

East Asian (EAS) AF: 0.466 AC: 2406 AN: 5168

South Asian (SAS) AF: 0.486 AC: 2329 AN: 4790

European-Finnish (FIN) AF: 0.401 AC: 4239 AN: 10564

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25938 AN: 67966

Other (OTH) AF: 0.410 AC: 865 AN: 2112

Alfa AF: 0.387 Hom.: 21469

Bravo AF: 0.422

Asia WGS AF: 0.477 AC: 1662 AN: 3478

EpiCase AF: 0.377

EpiControl AF: 0.380

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.89
DANN	Benign	0.49
PhyloP100		-0.12
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: rs2738100; hg19: chr8-6793581; COSMIC: COSV52404837;