20-3671118-C-T

Variant names:

• chr20-3671118-C-T
• rs3918396
• NM_025220.5:c.2128G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025220.5(ADAM33):​c.2128G>A​(p.Val710Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,606,170 control chromosomes in the GnomAD database, including 6,687 homozygotes. 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.067 (449 hom., cov: 34)
  • Exomes 𝑓: 0.088 (6238 hom.)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.27
• Publications: 53 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=0.0016098917).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5	c.2128G>A	p.Val710Ile	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.2128G>A	p.Val710Ile	missense_variant	Exon 19 of 22	1	NM_025220.5	ENSP00000348912.3
ADAM33	ENST00000379861.8	c.2128G>A	p.Val710Ile	missense_variant	Exon 19 of 22	1		ENSP00000369190.4
ADAM33	ENST00000466620.5	n.1689G>A		non_coding_transcript_exon_variant	Exon 8 of 11	1
ADAM33	ENST00000350009.6	c.2050G>A	p.Val684Ile	missense_variant	Exon 18 of 21	5		ENSP00000322550.5

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 10158 AN: 152158 Hom.: 449 Cov.: 34

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0510

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.0603

GnomAD2 exomes AF: 0.0763 AC: 17939 AN: 235174 AF XY: 0.0807

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.0325

Gnomad ASJ exome AF: 0.0705

Gnomad EAS exome AF: 0.0179

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0876

Gnomad OTH exome AF: 0.0781

GnomAD4 exome AF: 0.0880 AC: 127887 AN: 1453894 Hom.: 6238 Cov.: 36 AF XY: 0.0887 AC XY: 64090 AN XY: 722660

African (AFR) AF: 0.0124 AC: 415 AN: 33396

American (AMR) AF: 0.0337 AC: 1464 AN: 43444

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 1813 AN: 25932

East Asian (EAS) AF: 0.0107 AC: 421 AN: 39440

South Asian (SAS) AF: 0.114 AC: 9747 AN: 85274

European-Finnish (FIN) AF: 0.131 AC: 6867 AN: 52258

Middle Eastern (MID) AF: 0.0672 AC: 380 AN: 5652

European-Non Finnish (NFE) AF: 0.0919 AC: 101852 AN: 1108446

Other (OTH) AF: 0.0821 AC: 4928 AN: 60052

GnomAD4 genome AF: 0.0667 AC: 10161 AN: 152276 Hom.: 449 Cov.: 34 AF XY: 0.0693 AC XY: 5162 AN XY: 74450

African (AFR) AF: 0.0155 AC: 643 AN: 41578

American (AMR) AF: 0.0510 AC: 781 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 232 AN: 3472

East Asian (EAS) AF: 0.0182 AC: 94 AN: 5178

South Asian (SAS) AF: 0.109 AC: 526 AN: 4828

European-Finnish (FIN) AF: 0.143 AC: 1513 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0905 AC: 6150 AN: 67992

Other (OTH) AF: 0.0597 AC: 126 AN: 2112

Alfa AF: 0.0786 Hom.: 978

Bravo AF: 0.0568

TwinsUK AF: 0.0930 AC: 345

ALSPAC AF: 0.0906 AC: 349

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0881 AC: 757

ExAC AF: 0.0743 AC: 9009

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Uncertain:1

-

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Benign	0.71
DEOGEN2	Benign	0.041	T;.;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.64	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.060	N;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.47	N;N;.;N
REVEL	Benign	0.070
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.069	B;B;.;B
Vest4		0.044
MPC		0.048
ClinPred		0.0016	T
GERP RS		3.5
Varity_R		0.029
gMVP		0.39
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3918396; hg19: chr20-3651765; COSMIC: COSV62934543; COSMIC: COSV62934543;