rs3918396

chr20-3671118-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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=0.0016098917).
• 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/exons	MANE	UniProt
ADAM33	NM_025220.5	c.2128G>A	p.Val710Ile	missense_variant	19/22	ENST00000356518.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM33	ENST00000356518.7	c.2128G>A	p.Val710Ile	missense_variant	19/22	1	NM_025220.5	P4
ADAM33	ENST00000379861.8	c.2128G>A	p.Val710Ile	missense_variant	19/22	1		A2
ADAM33	ENST00000466620.5	n.1689G>A		non_coding_transcript_exon_variant	8/11	1
ADAM33	ENST00000350009.6	c.2050G>A	p.Val684Ile	missense_variant	18/21	5		A2

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

GnomAD3 exomes AF: 0.0763 AC: 17939 AN: 235174 Hom.: 901 AF XY: 0.0807 AC XY: 10305 AN XY: 127644

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 SAS exome AF: 0.114

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

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0337

Gnomad4 ASJ exome AF: 0.0699

Gnomad4 EAS exome AF: 0.0107

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.0919

Gnomad4 OTH exome AF: 0.0821

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

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0510

Gnomad4 ASJ AF: 0.0668

Gnomad4 EAS AF: 0.0182

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.0905

Gnomad4 OTH AF: 0.0597

Alfa AF: 0.0800 Hom.: 724

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

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

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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;.;.;.
MutationTaster	Benign	1.0	P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3918396; hg19: chr20-3651765; COSMIC: COSV62934543; COSMIC: COSV62934543;