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. Variant got 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. 14/21 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 Likely 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

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 made for transcript

Verdict is Uncertain_significance. Variant got 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

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

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

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

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over