Genetic Variant NM_025220.5:c.1543T>G (chr20-3672188-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025220.5(ADAM33):c.1543T>G(p.Trp515Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W515R) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADAM33
NM_025220.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.274

Publications

0 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: 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=0.25017774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5 link	c.1543T>G	p.Trp515Gly	missense_variant	Exon 14 of 22	ENST00000356518.7	NP_079496.1	Q9BZ11-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAM33	ENST00000356518.7 link	c.1543T>G	p.Trp515Gly	missense_variant	Exon 14 of 22	1	NM_025220.5	ENSP00000348912.3	Q9BZ11-1
ADAM33	ENST00000379861.8 link	c.1543T>G	p.Trp515Gly	missense_variant	Exon 14 of 22	1		ENSP00000369190.4	A2A2L3
ADAM33	ENST00000466620.5 link	n.1182T>G		non_coding_transcript_exon_variant	Exon 4 of 11	1
ADAM33	ENST00000350009.6 link	c.1543T>G	p.Trp515Gly	missense_variant	Exon 14 of 21	5		ENSP00000322550.5	Q9BZ11-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460936

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.22

T;.;T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.35

T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;.;.;L

PhyloP100

-0.27

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.5

D;D;.;D

REVEL

Benign

0.013

Sift

Uncertain

0.012

D;D;.;D

Sift4G

Benign

0.061

T;T;T;T

Polyphen

0.20

B;B;.;B

Vest4

0.48

MutPred

0.63

Gain of disorder (P = 0.0012);Gain of disorder (P = 0.0012);.;Gain of disorder (P = 0.0012);

MVP

0.19

MPC

0.16

ClinPred

0.16

GERP RS

0.17

Varity_R

0.38

gMVP

0.61

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over