chr5-179137837-C-A

Variant names:

• chr5-179137837-C-A
• NM_014244.5:c.1883G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014244.5(ADAMTS2):​c.1883G>T​(p.Arg628Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,252 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.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.827

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3373073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1883G>T	p.Arg628Leu	missense_variant	Exon 12 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1388G>T	p.Arg463Leu	missense_variant	Exon 11 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.1001G>T	p.Arg334Leu	missense_variant	Exon 10 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1883G>T	p.Arg628Leu	missense_variant	Exon 12 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.1883G>T	p.Arg628Leu	missense_variant	Exon 12 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.1883G>T		non_coding_transcript_exon_variant	Exon 12 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420252 Hom.: 0 Cov.: 42 AF XY: 0.00000142 AC XY: 1 AN XY: 702908

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: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.033
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.55	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.23
Sift	Benign	0.15	T;.
Sift4G	Benign	0.20	T;.
Polyphen		0.65	P;.
Vest4		0.58
MutPred		0.57		Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);
MVP		0.59
MPC		0.83
ClinPred		0.84	D
GERP RS		4.7
Varity_R		0.12
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-178564838;