rs2280091

chr20-3669587-A-Cchr20-3669587-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025220.5(ADAM33):c.2291T>G(p.Met764Arg) 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. 15/21 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. M764T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.729

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]

ACMG classification

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=0.111953616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM33	NM_025220.5	c.2291T>G	p.Met764Arg	missense_variant	20/22	ENST00000356518.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM33	ENST00000356518.7	c.2291T>G	p.Met764Arg	missense_variant	20/22	1	NM_025220.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	6.6
Dann	Benign	0.69
DEOGEN2	Benign	0.097	T;.;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N;N;.;N
REVEL	Benign	0.036
Sift	Uncertain	0.021	D;D;.;D
Sift4G	Benign	0.62	T;T;D;T
Polyphen		0.50	P;P;P;P
Vest4		0.27
MutPred		0.24		Loss of catalytic residue at M764 (P = 0.1615);Loss of catalytic residue at M764 (P = 0.1615);.;.;
MVP		0.11
MPC		0.17
ClinPred		0.12	T
GERP RS		1.2
Varity_R		0.29
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs2280091; hg19: chr20-3650234;