Genetic Variant ADAM33:p.Pro798Leu (chr20-3669310-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025220.5(ADAM33):c.2393C>T(p.Pro798Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAM33
NM_025220.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060658753).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025220.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAM33	NM_025220.5	MANE Select	c.2393C>T	p.Pro798Leu	missense	Exon 21 of 22	NP_079496.1
ADAM33	NM_001282447.3		c.2393C>T	p.Pro798Leu	missense	Exon 21 of 22	NP_001269376.1
ADAM33	NM_153202.4		c.2315C>T	p.Pro772Leu	missense	Exon 20 of 21	NP_694882.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAM33	ENST00000356518.7	TSL:1 MANE Select	c.2393C>T	p.Pro798Leu	missense	Exon 21 of 22	ENSP00000348912.3
ADAM33	ENST00000379861.8	TSL:1	c.2393C>T	p.Pro798Leu	missense	Exon 21 of 22	ENSP00000369190.4
ADAM33	ENST00000466620.5	TSL:1	n.1954C>T		non_coding_transcript_exon	Exon 10 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1444126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718162

African (AFR)

AF:

0.00

AC:

AN:

32246

American (AMR)

AF:

0.00

AC:

AN:

38458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25198

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

82722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107432

Other (OTH)

AF:

0.00

AC:

AN:

59664

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.15

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.65

M_CAP

Benign

0.012

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

0.020

REVEL

Benign

0.017

Sift

Benign

0.18

Sift4G

Uncertain

0.010

Polyphen

0.053

Vest4

0.065

MutPred

0.14

Loss of phosphorylation at S797 (P = 0.1628)

MVP

0.37

MPC

0.057

ClinPred

0.088

GERP RS

3.2

Varity_R

0.061

gMVP

0.14

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over