dbSNP rs745693841: DEFB105A:p.Ile4Asn (chr8-7823828-A-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_152250.3(DEFB105A):c.11T>A(p.Ile4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.070 ( 0 hom., cov: 0)

Exomes 𝑓: 0.26 ( 82 hom. )

Failed GnomAD Quality Control

Consequence

DEFB105A
NM_152250.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0470

Publications

3 publications found

Variant links:

Genes affected

DEFB105A (HGNC:18087): (defensin beta 105A) 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 105, DEFB105A and DEFB105B, in tail-to-tail orientation. This gene, DEFB105A, represents the more centromeric copy. [provided by RefSeq, Oct 2014]

DEFB105A links:

LOC124901865 (HGNC:):

LOC124901865 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015233755).

BP6

Variant 8-7823828-A-T is Benign according to our data. Variant chr8-7823828-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2226458.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEFB105A	NM_152250.3 link	c.11T>A	p.Ile4Asn	missense_variant	Exon 1 of 3	ENST00000334773.7	NP_689463.1	Q8NG35A0A0K0K1I4
LOC124901865		n.7823828A>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEFB105A	ENST00000334773.7 link	c.11T>A	p.Ile4Asn	missense_variant	Exon 1 of 3	1	NM_152250.3	ENSP00000334330.6		Q8NG35

Frequencies

GnomAD3 genomes

AF:

0.0741

AC:

AN:

162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0263

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.500

Gnomad EAS

AF:

0.143

Gnomad SAS

AF:

0.250

Gnomad FIN

AF:

0.00

Gnomad NFE

AF:

0.120

GnomAD2 exomes

AF:

0.275

AC:

1059

AN:

3854

AF XY:

0.271

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.308

Gnomad NFE exome

AF:

0.253

Gnomad OTH exome

AF:

0.213

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.264

AC:

20348

AN:

76958

Hom.:

Cov.:

AF XY:

0.266

AC XY:

10669

AN XY:

40176

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0672

AC:

119

AN:

1772

American (AMR)

AF:

0.284

AC:

1030

AN:

3622

Ashkenazi Jewish (ASJ)

AF:

0.283

AC:

542

AN:

1914

East Asian (EAS)

AF:

0.232

AC:

741

AN:

3198

South Asian (SAS)

AF:

0.287

AC:

2631

AN:

9154

European-Finnish (FIN)

AF:

0.307

AC:

1024

AN:

3340

Middle Eastern (MID)

AF:

0.218

AC:

AN:

248

European-Non Finnish (NFE)

AF:

0.265

AC:

13124

AN:

49528

Other (OTH)

AF:

0.259

AC:

1083

AN:

4182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.378

Heterozygous variant carriers

1048

2096

3143

4191

5239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0696

AC:

AN:

158

Hom.:

Cov.:

AF XY:

0.115

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0270

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.143

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.120

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000881), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.123

Hom.:

ExAC

AF:

0.0203

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 22, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.0

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.014

Eigen

Benign

-0.84

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0066

M_CAP

Benign

0.00079

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

PhyloP100

0.047

PrimateAI

Benign

0.29

PROVEAN

Benign

1.1

REVEL

Benign

0.0040

Sift

Benign

0.61

Sift4G

Benign

0.32

Vest4

0.027

MPC

0.53

ClinPred

0.0011

GERP RS

0.39

PromoterAI

0.033

Neutral

(source)

Varity_R

0.054

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over