20-158974-T-A

Variant names:

• chr20-158974-T-A
• NM_139074.4:c.250T>A

Variant summary

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

The NM_139074.4(DEFB127):​c.250T>A​(p.Tyr84Asn) 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. 14/21 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. Y84C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DEFB127 NM_139074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.04

Genes affected

DEFB127 (HGNC:16206): (defensin beta 127) 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 20p13. [provided by RefSeq, Nov 2014]

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=0.07261288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB127	NM_139074.4	c.250T>A	p.Tyr84Asn	missense_variant	Exon 2 of 2	ENST00000382388.4	NP_620713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFB127	ENST00000382388.4	c.250T>A	p.Tyr84Asn	missense_variant	Exon 2 of 2	1	NM_139074.4	ENSP00000371825.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.250T>A (p.Y84N) alteration is located in exon 2 (coding exon 2) of the DEFB127 gene. This alteration results from a T to A substitution at nucleotide position 250, causing the tyrosine (Y) at amino acid position 84 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	0.080
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.072
DANN	Benign	0.32
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.070
Sift	Benign	0.25	T
Sift4G	Benign	1.0	T
Polyphen		0.51	P
Vest4		0.10
MutPred		0.46		Gain of sheet (P = 0.0028);
MVP		0.014
MPC		0.043
ClinPred		0.95	D
GERP RS		-6.0
Varity_R		0.056
gMVP		0.50
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

Publications

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Other links and lift over

hg19: chr20-139615;