8-7016733-T-G

Variant names:

• chr8-7016733-T-G
• rs1810990173
• NM_005217.4:c.118A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005217.4(DEFA3):​c.118A>C​(p.Ile40Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DEFA3 NM_005217.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.898
• Publications: 0 publications found

Genes affected

DEFA3 (HGNC:2762): (defensin alpha 3) 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. The protein encoded by this gene, defensin, alpha 3, is found in the microbicidal granules of neutrophils and likely plays a role in phagocyte-mediated host defense. Several alpha defensin genes are clustered on chromosome 8. This gene differs from defensin, alpha 1 by only one amino acid. This gene and the gene encoding defensin, alpha 1 are both subject to copy number variation. [provided by RefSeq, Oct 2014]

LOC124901875 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14583582).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005217.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFA3	NM_005217.4	MANE Select	c.118A>C	p.Ile40Leu	missense	Exon 2 of 3	NP_005208.1	Q6EZE9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEFA3	ENST00000327857.7	TSL:1 MANE Select	c.118A>C	p.Ile40Leu	missense	Exon 2 of 3	ENSP00000328359.2	P59666
	DEFA3	ENST00000867396.1		c.118A>C	p.Ile40Leu	missense	Exon 1 of 2	ENSP00000537455.1
	DEFA3	ENST00000960561.1		c.118A>C	p.Ile40Leu	missense	Exon 3 of 4	ENSP00000630620.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.72e-7 AC: 1 AN: 1294800 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 642716

African (AFR) AF: 0.00 AC: 0 AN: 28026

American (AMR) AF: 0.00 AC: 0 AN: 33764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22424

East Asian (EAS) AF: 0.00 AC: 0 AN: 38822

South Asian (SAS) AF: 0.00 AC: 0 AN: 73254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3658

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 990402

Other (OTH) AF: 0.00 AC: 0 AN: 54088

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.4
DANN	Benign	0.85
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.90
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.052
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.67		Gain of loop (P = 0.1069)
MVP		0.20
MPC		1.7
ClinPred		0.33	T
GERP RS		-1.4
Varity_R		0.17
gMVP		0.059
Mutation Taster		=95/5	polymorphism

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: rs1810990173; hg19: chr8-6874255;