rs3918392

Variant names:

• chr20-3674572-T-C
• rs3918392
• NM_025220.5:c.532A>G

Variant summary

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

The NM_025220.5(ADAM33):​c.532A>G​(p.Thr178Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,613,380 control chromosomes in the GnomAD database, including 1,589 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.

• Frequency:
  • Genomes: 𝑓 0.051 (237 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1352 hom.)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.386
• Publications: 26 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=0.002142042).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 22	ENST00000356518.7	NP_079496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM33	ENST00000356518.7	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 22	1	NM_025220.5	ENSP00000348912.3
ADAM33	ENST00000379861.8	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 22	1		ENSP00000369190.4
ADAM33	ENST00000350009.6	c.532A>G	p.Thr178Ala	missense_variant	Exon 6 of 21	5		ENSP00000322550.5

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7673 AN: 152068 Hom.: 237 Cov.: 33

Gnomad AFR AF: 0.0780

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.0479

Gnomad EAS AF: 0.0843

Gnomad SAS AF: 0.0517

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0574

GnomAD2 exomes AF: 0.0447 AC: 11090 AN: 248154 AF XY: 0.0442

Gnomad AFR exome AF: 0.0799

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0548

Gnomad EAS exome AF: 0.0901

Gnomad FIN exome AF: 0.0254

Gnomad NFE exome AF: 0.0369

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0402 AC: 58772 AN: 1461194 Hom.: 1352 Cov.: 33 AF XY: 0.0405 AC XY: 29473 AN XY: 726896

African (AFR) AF: 0.0764 AC: 2555 AN: 33442

American (AMR) AF: 0.0343 AC: 1529 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0502 AC: 1311 AN: 26104

East Asian (EAS) AF: 0.0923 AC: 3665 AN: 39698

South Asian (SAS) AF: 0.0504 AC: 4346 AN: 86168

European-Finnish (FIN) AF: 0.0273 AC: 1452 AN: 53188

Middle Eastern (MID) AF: 0.0411 AC: 237 AN: 5766

European-Non Finnish (NFE) AF: 0.0368 AC: 40918 AN: 1111846

Other (OTH) AF: 0.0457 AC: 2759 AN: 60380

GnomAD4 genome AF: 0.0506 AC: 7694 AN: 152186 Hom.: 237 Cov.: 33 AF XY: 0.0505 AC XY: 3759 AN XY: 74404

African (AFR) AF: 0.0783 AC: 3251 AN: 41518

American (AMR) AF: 0.0497 AC: 760 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0479 AC: 166 AN: 3468

East Asian (EAS) AF: 0.0839 AC: 434 AN: 5172

South Asian (SAS) AF: 0.0517 AC: 249 AN: 4814

European-Finnish (FIN) AF: 0.0273 AC: 290 AN: 10604

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0351 AC: 2386 AN: 67990

Other (OTH) AF: 0.0592 AC: 125 AN: 2112

Alfa AF: 0.0420 Hom.: 397

Bravo AF: 0.0532

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.0788 AC: 347

ESP6500EA AF: 0.0344 AC: 296

ExAC AF: 0.0454 AC: 5514

Asia WGS AF: 0.0770 AC: 265 AN: 3478

EpiCase AF: 0.0361

EpiControl AF: 0.0383

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.70
DEOGEN2	Benign	0.071	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.018	T;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.39
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.63	N;N;.;N
REVEL	Benign	0.034
Sift	Benign	0.67	T;T;.;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.016
MPC		0.17
ClinPred		0.000016	T
GERP RS		2.0
Varity_R		0.022
gMVP		0.57
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3918392; hg19: chr20-3655219; COSMIC: COSV62934069; COSMIC: COSV62934069;