5-179154844-G-C

Variant names:

• chr5-179154844-G-C
• rs756455382
• NM_014244.5:c.1208C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014244.5(ADAMTS2):​c.1208C>G​(p.Ala403Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1208C>G	p.Ala403Gly	missense_variant	Exon 7 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.1208C>G	p.Ala403Gly	missense_variant	Exon 7 of 11		NP_067610.1
ADAMTS2	XM_047417895.1	c.713C>G	p.Ala238Gly	missense_variant	Exon 6 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.326C>G	p.Ala109Gly	missense_variant	Exon 5 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1208C>G	p.Ala403Gly	missense_variant	Exon 7 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.1208C>G	p.Ala403Gly	missense_variant	Exon 7 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.1208C>G	p.Ala403Gly	missense_variant	Exon 7 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.1208C>G		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0090	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.74
MutPred		0.91		Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);
MVP		0.81
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs756455382; hg19: chr5-178581845;