NM_025220.5:c.1543T>C

Variant names:

• chr20-3672188-A-G
• rs615436
• NM_025220.5:c.1543T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025220.5(ADAM33):​c.1543T>C​(p.Trp515Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,613,268 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.019 (96 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (109 hom.)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.274

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002875179).
• BP6: Variant 20-3672188-A-G is Benign according to our data. Variant chr20-3672188-A-G is described in ClinVar as [Benign]. Clinvar id is 785649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM33	NM_025220.5	c.1543T>C	p.Trp515Arg	missense_variant	Exon 14 of 22	ENST00000356518.7	NP_079496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM33	ENST00000356518.7	c.1543T>C	p.Trp515Arg	missense_variant	Exon 14 of 22	1	NM_025220.5	ENSP00000348912.3
ADAM33	ENST00000379861.8	c.1543T>C	p.Trp515Arg	missense_variant	Exon 14 of 22	1		ENSP00000369190.4
ADAM33	ENST00000466620.5	n.1182T>C		non_coding_transcript_exon_variant	Exon 4 of 11	1
ADAM33	ENST00000350009.6	c.1543T>C	p.Trp515Arg	missense_variant	Exon 14 of 21	5		ENSP00000322550.5

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2847 AN: 152214 Hom.: 96 Cov.: 33

Gnomad AFR AF: 0.0661

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00456 AC: 1138 AN: 249614 Hom.: 49 AF XY: 0.00338 AC XY: 458 AN XY: 135372

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00190 AC: 2773 AN: 1460936 Hom.: 109 Cov.: 35 AF XY: 0.00162 AC XY: 1174 AN XY: 726786

Gnomad4 AFR exome AF: 0.0711

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.0187 AC: 2847 AN: 152332 Hom.: 96 Cov.: 33 AF XY: 0.0187 AC XY: 1394 AN XY: 74482

Gnomad4 AFR AF: 0.0659

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00603 Hom.: 23

Bravo AF: 0.0212

ESP6500AA AF: 0.0615 AC: 271

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00574 AC: 697

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.4
DANN	Benign	0.76
DEOGEN2	Benign	0.21	T;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.045	T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.48	N;.;.;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N;N;.;N
REVEL	Benign	0.028
Sift	Benign	0.17	T;T;.;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.31
MutPred		0.40		Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);.;Gain of disorder (P = 0.0017);
MVP		0.28
MPC		0.089
ClinPred		0.0024	T
GERP RS		0.17
Varity_R		0.15
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs615436; hg19: chr20-3652835; COSMIC: COSV62935439; COSMIC: COSV62935439;