rs745588970

Positions:

• chr5-179344101-T-A
• chr5-179344101-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000251582.12(ADAMTS2):​c.200A>T​(p.Gln67Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q67R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADAMTS2 ENST00000251582.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13811389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.200A>T	p.Gln67Leu	missense_variant	2/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.200A>T	p.Gln67Leu	missense_variant	2/11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.200A>T	p.Gln67Leu	missense_variant	2/22	1	NM_014244.5	ENSP00000251582	P2
ADAMTS2	ENST00000274609.5	c.200A>T	p.Gln67Leu	missense_variant	2/11	1		ENSP00000274609
ADAMTS2	ENST00000518335.3	c.200A>T	p.Gln67Leu	missense_variant	2/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1	c.200A>T	p.Gln67Leu	missense_variant, NMD_transcript_variant	2/21			ENSP00000514008

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000171 AC: 4 AN: 233578 Hom.: 0 AF XY: 0.0000156 AC XY: 2 AN XY: 128536

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456988 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000837 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.24	T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	0.80	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Benign	0.12
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.13	T;.;T
Polyphen		0.0010	B;.;B
Vest4		0.27
MutPred		0.48		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.47
MPC		0.52
ClinPred		0.096	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs745588970; hg19: chr5-178771102;