20-96275-C-A

Variant names:

• chr20-96275-C-A
• rs1237850673
• NM_153325.4:c.329C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153325.4(DEFB125):​c.329C>A​(p.Thr110Asn) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T110S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DEFB125 NM_153325.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.747

Genes affected

DEFB125 (HGNC:18105): (defensin beta 125) Defensins are cysteine-rich cationic polypeptides that are important in the host 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 20p13. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043780476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB125	NM_153325.4	c.329C>A	p.Thr110Asn	missense_variant	Exon 2 of 2	ENST00000382410.3	NP_697020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFB125	ENST00000382410.3	c.329C>A	p.Thr110Asn	missense_variant	Exon 2 of 2	1	NM_153325.4	ENSP00000371847.2
DEFB125	ENST00000608838.1	n.381C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461878 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.329C>A (p.T110N) alteration is located in exon 2 (coding exon 2) of the DEFB125 gene. This alteration results from a C to A substitution at nucleotide position 329, causing the threonine (T) at amino acid position 110 to be replaced by an asparagine (N). 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	0.091
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.85
DANN	Benign	0.84
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.0060
Sift	Benign	0.035	D
Sift4G	Benign	0.12	T
Polyphen		0.0080	B
Vest4		0.027
MutPred		0.17		Loss of glycosylation at T110 (P = 0.0057);
MVP		0.048
MPC		0.35
ClinPred		0.23	T
GERP RS		-3.5
Varity_R		0.066
gMVP		0.039

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: rs1237850673; hg19: chr20-76916;