Variant 20-3671899-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025220.5(ADAM33):c.1684C>G(p.His562Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,401,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ADAM33
NM_025220.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0190

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=0.11684069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM33	NM_025220.5 linkuse as main transcript	c.1684C>G	p.His562Asp	missense_variant	15/22	ENST00000356518.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM33	ENST00000356518.7 linkuse as main transcript	c.1684C>G	p.His562Asp	missense_variant	15/22	1	NM_025220.5	P4	Q9BZ11-1
ADAM33	ENST00000379861.8 linkuse as main transcript	c.1684C>G	p.His562Asp	missense_variant	15/22	1		A2
ADAM33	ENST00000466620.5 linkuse as main transcript	n.1323C>G		non_coding_transcript_exon_variant	5/11	1
ADAM33	ENST00000350009.6 linkuse as main transcript	c.1684C>G	p.His562Asp	missense_variant	15/21	5		A2	Q9BZ11-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

159794

Hom.:

AF XY:

0.0000238

AC XY:

AN XY:

84140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000872

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000357

AC:

AN:

1401562

Hom.:

Cov.:

AF XY:

0.00000578

AC XY:

AN XY:

691462

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:

0.0000630

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000919

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.1684C>G (p.H562D) alteration is located in exon 15 (coding exon 15) of the ADAM33 gene. This alteration results from a C to G substitution at nucleotide position 1684, causing the histidine (H) at amino acid position 562 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.7

DANN

Benign

0.71

DEOGEN2

Benign

0.032

T;.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.39

T;T;T;T

M_CAP

Benign

0.0068

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.46

N;.;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.88

N;N;.;N

REVEL

Benign

0.027

Sift

Benign

0.16

T;T;.;T

Sift4G

Benign

0.39

T;T;T;T

Polyphen

0.065

B;B;.;B

Vest4

0.17

MutPred

0.44

Loss of catalytic residue at H562 (P = 0.0325);Loss of catalytic residue at H562 (P = 0.0325);.;Loss of catalytic residue at H562 (P = 0.0325);

MVP

0.18

MPC

0.070

ClinPred

0.065

GERP RS

-10

Varity_R

0.047

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over