chr20-3671128-C-T

Variant names:

• chr20-3671128-C-T
• NM_025220.5:c.2118G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025220.5(ADAM33):​c.2118G>A​(p.Met706Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034798503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5	c.2118G>A	p.Met706Ile	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.2118G>A	p.Met706Ile	missense_variant	Exon 19 of 22	1	NM_025220.5	ENSP00000348912.3
ADAM33	ENST00000379861.8	c.2118G>A	p.Met706Ile	missense_variant	Exon 19 of 22	1		ENSP00000369190.4
ADAM33	ENST00000466620.5	n.1679G>A		non_coding_transcript_exon_variant	Exon 8 of 11	1
ADAM33	ENST00000350009.6	c.2040G>A	p.Met680Ile	missense_variant	Exon 18 of 21	5		ENSP00000322550.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2118G>A (p.M706I) 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 2118, causing the methionine (M) at amino acid position 706 to be replaced by an isoleucine (I). 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	0.33
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.66
DEOGEN2	Benign	0.040	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.14	N;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.26	N;N;.;N
REVEL	Benign	0.042
Sift	Benign	0.80	T;T;.;T
Sift4G	Benign	0.88	T;T;T;T
Polyphen		0.070	B;B;.;B
Vest4		0.057
MutPred		0.47		Gain of catalytic residue at L711 (P = 0.031);Gain of catalytic residue at L711 (P = 0.031);.;.;
MVP		0.13
MPC		0.062
ClinPred		0.029	T
GERP RS		0.89
Varity_R		0.049
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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.

Other links and lift over

hg19: chr20-3651775;