20-3671034-C-T

Variant names:

• chr20-3671034-C-T
• rs1186574586
• NM_025220.5:c.2212G>A

Variant summary

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

The NM_025220.5(ADAM33):​c.2212G>A​(p.Gly738Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,403,780 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: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.979

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=0.071799725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5	c.2212G>A	p.Gly738Ser	missense_variant	Exon 19 of 22	ENST00000356518.7	NP_079496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM33	ENST00000356518.7	c.2212G>A	p.Gly738Ser	missense_variant	Exon 19 of 22	1	NM_025220.5	ENSP00000348912.3
ADAM33	ENST00000379861.8	c.2212G>A	p.Gly738Ser	missense_variant	Exon 19 of 22	1		ENSP00000369190.4
ADAM33	ENST00000466620.5	n.1773G>A		non_coding_transcript_exon_variant	Exon 8 of 11	1
ADAM33	ENST00000350009.6	c.2134G>A	p.Gly712Ser	missense_variant	Exon 18 of 21	5		ENSP00000322550.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1403780 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 693212

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: 0.0000206

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2212G>A (p.G738S) alteration is located in exon 19 (coding exon 19) of the ADAM33 gene. This alteration results from a G to A substitution at nucleotide position 2212, causing the glycine (G) at amino acid position 738 to be replaced by a serine (S). 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	0.089
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.9
DANN	Benign	0.96
DEOGEN2	Benign	0.090	T;.;T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N;N;.;N
REVEL	Benign	0.021
Sift	Benign	0.41	T;T;.;T
Sift4G	Benign	0.83	T;T;T;T
Polyphen		0.062	B;B;.;B
Vest4		0.12
MutPred		0.21		Gain of phosphorylation at G738 (P = 0.0723);Gain of phosphorylation at G738 (P = 0.0723);.;.;
MVP		0.15
MPC		0.069
ClinPred		0.089	T
GERP RS		2.6
Varity_R		0.037
gMVP		0.43

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

Other links and lift over

dbSNP: rs1186574586; hg19: chr20-3651681;