rs35445112

Positions:

• chr5-179128096-C-A
• chr5-179128096-C-T

Variant summary

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

The NM_014244.5(ADAMTS2):​c.2480G>T​(p.Arg827Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R827Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.2480G>T	p.Arg827Leu	missense_variant	17/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1985G>T	p.Arg662Leu	missense_variant	16/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.1598G>T	p.Arg533Leu	missense_variant	15/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2480G>T	p.Arg827Leu	missense_variant	17/22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.2480G>T	p.Arg827Leu	missense_variant	17/21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.2480G>T		non_coding_transcript_exon_variant	17/21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461496 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	0.015
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Benign	0.21
Sift	Benign	0.039	D;.
Sift4G	Uncertain	0.037	D;.
Polyphen		0.56	P;.
Vest4		0.46
MutPred		0.61		Loss of phosphorylation at T826 (P = 0.3492);Loss of phosphorylation at T826 (P = 0.3492);
MVP		0.50
MPC		0.79
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.31
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35445112; hg19: chr5-178555097;