5-179153579-G-C

Variant names:

• chr5-179153579-G-C
• rs762123346
• NM_014244.5:c.1427C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014244.5(ADAMTS2):​c.1427C>G​(p.Pro476Arg) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P476L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 0 publications found

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]

ADAMTS2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, dermatosparaxis type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.1427C>G	p.Pro476Arg	missense	Exon 9 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.1427C>G	p.Pro476Arg	missense	Exon 9 of 11	NP_067610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1427C>G	p.Pro476Arg	missense	Exon 9 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.1427C>G	p.Pro476Arg	missense	Exon 9 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000518335.3	TSL:3	c.1427C>G	p.Pro476Arg	missense	Exon 9 of 21	ENSP00000489888.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.78
Sift	Benign	0.052	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.69		Loss of catalytic residue at W475 (P = 0.0848)
MVP		0.82
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.43
gMVP		0.84
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs762123346; hg19: chr5-178580580;