Variant 8-7016823-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005217.4(DEFA3):c.28A>C(p.Ile10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.013 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DEFA3
NM_005217.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.598

Variant links:

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]

DEFA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029273331).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFA3	NM_005217.4 linkuse as main transcript	c.28A>C	p.Ile10Leu	missense_variant	2/3	ENST00000327857.7	NP_005208.1	P59666Q6EZE9
DEFA3	XM_011534741.3 linkuse as main transcript	c.49A>C	p.Ile17Leu	missense_variant	3/4		XP_011533043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEFA3	ENST00000327857.7 linkuse as main transcript	c.28A>C	p.Ile10Leu	missense_variant	2/3	1	NM_005217.4	ENSP00000328359.2		P59666

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

1750

AN:

134230

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0526

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00456

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00333

Gnomad NFE

AF:

0.000110

Gnomad OTH

AF:

0.00613

GnomAD3 exomes

AF:

0.000768

AC:

AN:

42976

Hom.:

AF XY:

0.000500

AC XY:

AN XY:

21982

show subpopulations

Gnomad AFR exome

AF:

0.00962

Gnomad AMR exome

AF:

0.000833

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000568

Gnomad OTH exome

AF:

0.000684

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00111

AC:

1276

AN:

1150844

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

563

AN XY:

565222

show subpopulations

Gnomad4 AFR exome

AF:

0.0472

Gnomad4 AMR exome

AF:

0.00375

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000815

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000676

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0131

AC:

1755

AN:

134320

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

831

AN XY:

65346

show subpopulations

Gnomad4 AFR

AF:

0.0526

Gnomad4 AMR

AF:

0.00456

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000110

Gnomad4 OTH

AF:

0.00606

ExAC

AF:

0.0000324

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.28A>C (p.I10L) alteration is located in exon 2 (coding exon 1) of the DEFA3 gene. This alteration results from a A to C substitution at nucleotide position 28, causing the isoleucine (I) at amino acid position 10 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.3

DANN

Benign

0.94

DEOGEN2

Benign

0.017

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.37

M_CAP

Benign

0.00077

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.98

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.62

REVEL

Benign

0.11

Sift

Benign

0.27

Sift4G

Benign

0.32

Polyphen

0.012

Vest4

0.28

MutPred

0.75

Gain of disorder (P = 0.0627);

MVP

0.20

MPC

2.2

ClinPred

0.0012

GERP RS

-4.1

Varity_R

0.059

gMVP

0.043

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over