20-3669587-A-G

Variant names:

• chr20-3669587-A-G
• rs2280091
• NM_025220.5:c.2291T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025220.5(ADAM33):​c.2291T>C​(p.Met764Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,602,084 control chromosomes in the GnomAD database, including 14,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1383 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13210 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004139662).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5	c.2291T>C	p.Met764Thr	missense_variant	Exon 20 of 22	ENST00000356518.7	NP_079496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM33	ENST00000356518.7	c.2291T>C	p.Met764Thr	missense_variant	Exon 20 of 22	1	NM_025220.5	ENSP00000348912.3

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20592 AN: 151612 Hom.: 1382 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.0990

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.130 AC: 29538 AN: 227930 Hom.: 2019 AF XY: 0.134 AC XY: 16488 AN XY: 122934

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.0666

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0858

Gnomad SAS exome AF: 0.172

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.133 AC: 192737 AN: 1450352 Hom.: 13210 Cov.: 33 AF XY: 0.135 AC XY: 97280 AN XY: 720044

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.0705

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.136 AC: 20599 AN: 151732 Hom.: 1383 Cov.: 32 AF XY: 0.136 AC XY: 10115 AN XY: 74120

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.0993

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.146

Alfa AF: 0.131 Hom.: 811

Bravo AF: 0.126

TwinsUK AF: 0.128 AC: 475

ALSPAC AF: 0.127 AC: 489

ESP6500AA AF: 0.135 AC: 595

ESP6500EA AF: 0.133 AC: 1146

ExAC AF: 0.126 AC: 15154

Asia WGS AF: 0.128 AC: 444 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.5
DANN	Benign	0.29
DEOGEN2	Benign	0.064	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.48	T;T;T;T
MetaRNN	Benign	0.0041	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.84	N;N;.;N
REVEL	Benign	0.022
Sift	Benign	0.15	T;T;.;T
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.081	B;B;P;B
Vest4		0.094
MPC		0.061
ClinPred		0.00023	T
GERP RS		1.2
Varity_R		0.051
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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; COSMIC: COSV62934362;