Genetic Variant NM_025220.5:c.532A>G (chr20-3674572-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_025220.5(ADAM33):c.532A>G(p.Thr178Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,613,380 control chromosomes in the GnomAD database, including 1,589 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.051 ( 237 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1352 hom. )

Consequence

ADAM33
NM_025220.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.386

Publications

26 publications found

Variant links:

Genes affected

ADAM33 (HGNC:15478): (ADAM metallopeptidase domain 33) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This protein is a type I transmembrane protein implicated in asthma and bronchial hyperresponsiveness. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

ADAM33 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002142042).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5 link	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 22	ENST00000356518.7	NP_079496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ADAM33	ENST00000356518.7 link	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 22	1	NM_025220.5	ENSP00000348912.3
ADAM33	ENST00000379861.8 link	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 22	1		ENSP00000369190.4
ADAM33	ENST00000350009.6 link	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 21	5		ENSP00000322550.5

Frequencies

GnomAD3 genomes

AF:

0.0505

AC:

7673

AN:

152068

Hom.:

237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0780

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0497

Gnomad ASJ

AF:

0.0479

Gnomad EAS

AF:

0.0843

Gnomad SAS

AF:

0.0517

Gnomad FIN

AF:

0.0273

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0574

GnomAD2 exomes

AF:

0.0447

AC:

11090

AN:

248154

AF XY:

0.0442

show subpopulations

Gnomad AFR exome

AF:

0.0799

Gnomad AMR exome

AF:

0.0332

Gnomad ASJ exome

AF:

0.0548

Gnomad EAS exome

AF:

0.0901

Gnomad FIN exome

AF:

0.0254

Gnomad NFE exome

AF:

0.0369

Gnomad OTH exome

AF:

0.0399

GnomAD4 exome

AF:

0.0402

AC:

58772

AN:

1461194

Hom.:

1352

Cov.:

AF XY:

0.0405

AC XY:

29473

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.0764

AC:

2555

AN:

33442

American (AMR)

AF:

0.0343

AC:

1529

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.0502

AC:

1311

AN:

26104

East Asian (EAS)

AF:

0.0923

AC:

3665

AN:

39698

South Asian (SAS)

AF:

0.0504

AC:

4346

AN:

86168

European-Finnish (FIN)

AF:

0.0273

AC:

1452

AN:

53188

Middle Eastern (MID)

AF:

0.0411

AC:

237

AN:

5766

European-Non Finnish (NFE)

AF:

0.0368

AC:

40918

AN:

1111846

Other (OTH)

AF:

0.0457

AC:

2759

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3666

7331

10997

14662

18328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1640

3280

4920

6560

8200

<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

AF:

0.0506

AC:

7694

AN:

152186

Hom.:

237

Cov.:

AF XY:

0.0505

AC XY:

3759

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0783

AC:

3251

AN:

41518

American (AMR)

AF:

0.0497

AC:

760

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0479

AC:

166

AN:

3468

East Asian (EAS)

AF:

0.0839

AC:

434

AN:

5172

South Asian (SAS)

AF:

0.0517

AC:

249

AN:

4814

European-Finnish (FIN)

AF:

0.0273

AC:

290

AN:

10604

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0351

AC:

2386

AN:

67990

Other (OTH)

AF:

0.0592

AC:

125

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

369

738

1108

1477

1846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0420

Hom.:

397

Bravo

AF:

0.0532

TwinsUK

AF:

0.0359

AC:

133

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.0788

AC:

347

ESP6500EA

AF:

0.0344

AC:

296

ExAC

AF:

0.0454

AC:

5514

Asia WGS

AF:

0.0770

AC:

265

AN:

3478

EpiCase

AF:

0.0361

EpiControl

AF:

0.0383

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.60

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.071

T;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.018

T;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

-0.39

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.63

N;N;.;N

REVEL

Benign

0.034

Sift

Benign

0.67

T;T;.;T

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.016

MPC

0.17

ClinPred

0.000016

GERP RS

2.0

Varity_R

0.022

gMVP

0.57

Mutation Taster

=99/1

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over