4-9450437-G-A

Position:

• chr4-9450437-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040448.3(DEFB131A):​c.136G>A​(p.Ala46Thr) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DEFB131A NM_001040448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0520

Genes affected

DEFB131A (HGNC:18108): (defensin beta 131A) Defensins are cysteine-rich cationic polypeptides that are important in the immunologic response to invading microorganisms. The antimicrobial protein encoded by this gene is secreted and is a member of the beta defensin protein family. Beta defensin genes are found in several clusters throughout the genome, with this gene mapping to a cluster at 4p16. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15341815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFB131A	NM_001040448.3	c.136G>A	p.Ala46Thr	missense_variant	2/2	ENST00000334879.2	NP_001035538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEFB131A	ENST00000334879.2	c.136G>A	p.Ala46Thr	missense_variant	2/2	1	NM_001040448.3	ENSP00000335538.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000206 AC: 3 AN: 1458048 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725130

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.136G>A (p.A46T) alteration is located in exon 2 (coding exon 2) of the DEFB131 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the alanine (A) at amino acid position 46 to be replaced by a threonine (T). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.1
DANN	Benign	0.88
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.85	P
Vest4		0.44
MutPred		0.31		Loss of helix (P = 0.0068);
MVP		0.030
MPC		0.00037
ClinPred		0.66	D
GERP RS		0.44
Varity_R		0.35
gMVP		0.080

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

Other links and lift over

dbSNP: rs1717628041; hg19: chr4-9452163;