NM_025220.5:c.2291T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 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.

• 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
• Publications: 78 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025220.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM33	NM_025220.5	MANE Select	c.2291T>C	p.Met764Thr	missense	Exon 20 of 22	NP_079496.1	Q9BZ11-1
	ADAM33	NM_001282447.3		c.2291T>C	p.Met764Thr	missense	Exon 20 of 22	NP_001269376.1	A2A2L3
	ADAM33	NM_153202.4		c.2213T>C	p.Met738Thr	missense	Exon 19 of 21	NP_694882.1	Q9BZ11-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM33	ENST00000356518.7	TSL:1 MANE Select	c.2291T>C	p.Met764Thr	missense	Exon 20 of 22	ENSP00000348912.3	Q9BZ11-1
	ADAM33	ENST00000379861.8	TSL:1	c.2291T>C	p.Met764Thr	missense	Exon 20 of 22	ENSP00000369190.4	A2A2L3
	ADAM33	ENST00000466620.5	TSL:1	n.1852T>C		non_coding_transcript_exon	Exon 9 of 11

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

GnomAD2 exomes AF: 0.130 AC: 29538 AN: 227930 AF XY: 0.134

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 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

African (AFR) AF: 0.129 AC: 4316 AN: 33418

American (AMR) AF: 0.0705 AC: 3029 AN: 42950

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3876 AN: 25658

East Asian (EAS) AF: 0.112 AC: 4417 AN: 39382

South Asian (SAS) AF: 0.175 AC: 14634 AN: 83524

European-Finnish (FIN) AF: 0.174 AC: 9094 AN: 52336

Middle Eastern (MID) AF: 0.200 AC: 1145 AN: 5738

European-Non Finnish (NFE) AF: 0.130 AC: 144000 AN: 1107396

Other (OTH) AF: 0.137 AC: 8226 AN: 59950

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

African (AFR) AF: 0.133 AC: 5502 AN: 41382

American (AMR) AF: 0.109 AC: 1663 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 501 AN: 3464

East Asian (EAS) AF: 0.0993 AC: 504 AN: 5078

South Asian (SAS) AF: 0.163 AC: 782 AN: 4810

European-Finnish (FIN) AF: 0.167 AC: 1769 AN: 10580

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.138 AC: 9385 AN: 67836

Other (OTH) AF: 0.146 AC: 307 AN: 2106

Alfa AF: 0.129 Hom.: 1171

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 v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.73
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.022
Sift	Benign	0.15	T
Sift4G	Benign	0.68	T
Polyphen		0.081	B
Vest4		0.094
MPC		0.061
ClinPred		0.00023	T
GERP RS		1.2
Varity_R		0.051
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2280091; hg19: chr20-3650234; COSMIC: COSV62934362;