rs2280090

Variant names:

• chr20-3669558-G-A
• rs2280090
• NM_025220.5:c.2320C>T

Variant summary

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

The NM_025220.5(ADAM33):​c.2320C>T​(p.Pro774Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,593,874 control chromosomes in the GnomAD database, including 14,779 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 (1465 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13314 hom.)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139

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=0.0043251216).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5	c.2320C>T	p.Pro774Ser	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.2320C>T	p.Pro774Ser	missense_variant	Exon 20 of 22	1	NM_025220.5	ENSP00000348912.3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21177 AN: 151882 Hom.: 1465 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.131 AC: 28338 AN: 216304 Hom.: 1937 AF XY: 0.135 AC XY: 15700 AN XY: 116194

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0657

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.0967

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.134 AC: 192711 AN: 1441876 Hom.: 13314 Cov.: 33 AF XY: 0.136 AC XY: 97147 AN XY: 715076

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0703

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.139 AC: 21183 AN: 151998 Hom.: 1465 Cov.: 32 AF XY: 0.140 AC XY: 10410 AN XY: 74286

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.148

Alfa AF: 0.139 Hom.: 667

Bravo AF: 0.131

TwinsUK AF: 0.128 AC: 473

ALSPAC AF: 0.127 AC: 489

ESP6500AA AF: 0.142 AC: 627

ESP6500EA AF: 0.132 AC: 1134

ExAC AF: 0.123 AC: 14813

Asia WGS AF: 0.136 AC: 474 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.89
DEOGEN2	Benign	0.20	T;.;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.63	T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.77	N;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.3	D;D;.;D
REVEL	Benign	0.036
Sift	Benign	0.17	T;T;.;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.036	B;B;P;B
Vest4		0.037
MPC		0.059
ClinPred		0.0018	T
GERP RS		-0.23
Varity_R		0.045
gMVP		0.54

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: rs2280090; hg19: chr20-3650205; COSMIC: COSV62934354;