Genetic Variant DEFB104B:p.Thr34Ile (chr8-7470474-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001040702.1(DEFB104B):c.101C>T(p.Thr34Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 2)

Exomes 𝑓: 0.0014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DEFB104B
NM_001040702.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64

Variant links:

Genes affected

DEFB104B (HGNC:26165): (defensin beta 104B) Defensins form a family of antimicrobial and cytotoxic peptides made by neutrophils. Defensins are short, processed peptide molecules that are classified by structure into three groups: alpha-defensins, beta-defensins and theta-defensins. All beta-defensin genes are densely clustered in four to five syntenic chromosomal regions. Chromosome 8p23 contains at least two copies of the duplicated beta-defensin cluster. This duplication results in two identical copies of defensin, beta 104, DEFB104A and DEFB104B, in head-to-head orientation. This gene, DEFB104B, represents the more telomeric copy. [provided by RefSeq, Oct 2014]

DEFB104B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11798793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB104B	NM_001040702.1 link	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 2	ENST00000316169.2	NP_001035792.1	Q8WTQ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFB104B	ENST00000316169.2 link	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 2	1	NM_001040702.1	ENSP00000322191.2		Q8WTQ1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

4968

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00246

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.0135

GnomAD3 exomes

AF:

0.00108

AC:

AN:

21222

Hom.:

AF XY:

0.00123

AC XY:

AN XY:

11376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000638

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00163

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00138

AC:

251

AN:

181282

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

121

AN XY:

94256

show subpopulations

Gnomad4 AFR exome

AF:

0.000465

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000152

Gnomad4 FIN exome

AF:

0.000799

Gnomad4 NFE exome

AF:

0.00182

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000805

AC:

AN:

4970

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

AN XY:

2050

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.0139

Alfa

AF:

0.000253

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.101C>T (p.T34I) alteration is located in exon 2 (coding exon 2) of the DEFB104B gene. This alteration results from a C to T substitution at nucleotide position 101, causing the threonine (T) at amino acid position 34 to be replaced by an isoleucine (I). 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

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

0.15

Eigen_PC

Benign

-0.032

FATHMM_MKL

Benign

0.55

M_CAP

Benign

0.012

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.2

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.091

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.53

MutPred

0.33

Loss of phosphorylation at T34 (P = 0.0342);

MVP

0.31

ClinPred

0.25

GERP RS

2.1

gMVP

0.054

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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