8-7016700-C-G

Variant names:

• chr8-7016700-C-G
• rs1228189820
• NM_005217.4:c.151G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005217.4(DEFA3):​c.151G>C​(p.Glu51Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E51K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DEFA3 NM_005217.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.432
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062851846).

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.151G>C	p.Glu51Gln	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.151G>C	p.Glu51Gln	missense	Exon 2 of 3	ENSP00000328359.2	P59666
	DEFA3	ENST00000867396.1		c.151G>C	p.Glu51Gln	missense	Exon 1 of 2	ENSP00000537455.1
	DEFA3	ENST00000960561.1		c.151G>C	p.Glu51Gln	missense	Exon 3 of 4	ENSP00000630620.1

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 17 AN: 146574 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000436

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 1 AN: 81700 AF XY: 0.0000236

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000168 AC: 219 AN: 1306560 Hom.: 0 Cov.: 27 AF XY: 0.000181 AC XY: 117 AN XY: 648116

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

African (AFR) AF: 0.0000358 AC: 1 AN: 27900

American (AMR) AF: 0.000121 AC: 4 AN: 33026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22150

East Asian (EAS) AF: 0.00 AC: 0 AN: 38960

South Asian (SAS) AF: 0.000388 AC: 28 AN: 72224

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50386

Middle Eastern (MID) AF: 0.000273 AC: 1 AN: 3660

European-Non Finnish (NFE) AF: 0.000175 AC: 176 AN: 1003818

Other (OTH) AF: 0.000147 AC: 8 AN: 54436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000123 AC: 18 AN: 146692 Hom.: 0 Cov.: 27 AF XY: 0.000126 AC XY: 9 AN XY: 71618

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

African (AFR) AF: 0.0000509 AC: 2 AN: 39282

American (AMR) AF: 0.0000687 AC: 1 AN: 14554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000655 AC: 3 AN: 4580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000181 AC: 12 AN: 66266

Other (OTH) AF: 0.00 AC: 0 AN: 1984

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000612 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	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.23
DANN	Benign	0.71
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.43
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.012
Sift	Benign	0.21	T
Sift4G	Benign	0.16	T
Polyphen		0.045	B
Vest4		0.063
MVP		0.22
MPC		1.8
ClinPred		0.035	T
GERP RS		1.1
Varity_R		0.054
gMVP		0.14
Mutation Taster		=99/1	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: rs1228189820; hg19: chr8-6874222;