20-3671284-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025220.5(ADAM33):c.2045A>C(p.Lys682Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,613,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00058 (1 hom.)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.708

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034207165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM33	NM_025220.5	c.2045A>C	p.Lys682Thr	missense_variant	18/22	ENST00000356518.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM33	ENST00000356518.7	c.2045A>C	p.Lys682Thr	missense_variant	18/22	1	NM_025220.5	P4
ADAM33	ENST00000379861.8	c.2045A>C	p.Lys682Thr	missense_variant	18/22	1		A2
ADAM33	ENST00000466620.5	n.1606A>C		non_coding_transcript_exon_variant	7/11	1
ADAM33	ENST00000350009.6	c.1967A>C	p.Lys656Thr	missense_variant	17/21	5		A2

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251176 Hom.: 0 AF XY: 0.000456 AC XY: 62 AN XY: 135830

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000580 AC: 848 AN: 1461588 Hom.: 1 Cov.: 36 AF XY: 0.000604 AC XY: 439 AN XY: 727104

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.0000941

Gnomad4 NFE exome AF: 0.000621

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152322 Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.2045A>C (p.K682T) alteration is located in exon 18 (coding exon 18) of the ADAM33 gene. This alteration results from a A to C substitution at nucleotide position 2045, causing the lysine (K) at amino acid position 682 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.38	T;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.5	D;D;.;D
REVEL	Benign	0.26
Sift	Benign	0.27	T;T;.;T
Sift4G	Benign	0.21	T;T;D;T
Polyphen		0.76	P;P;.;P
Vest4		0.34
MVP		0.78
MPC		0.13
ClinPred		0.10	T
GERP RS		4.6
Varity_R		0.29
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs201057173; hg19: chr20-3651931;