5-179137817-C-G

Variant names:

• chr5-179137817-C-G
• rs371099308
• NM_014244.5:c.1903G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014244.5(ADAMTS2):​c.1903G>C​(p.Glu635Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,427,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E635G) has been classified as Uncertain significance.

• 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: 0.806
• 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), G2P, Orphanet, Illumina, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35320657).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.1903G>C	p.Glu635Gln	missense	Exon 12 of 22	NP_055059.2	O95450-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1903G>C	p.Glu635Gln	missense	Exon 12 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000957641.1		c.1903G>C	p.Glu635Gln	missense	Exon 12 of 22	ENSP00000627700.1
	ADAMTS2	ENST00000518335.3	TSL:3	c.1903G>C	p.Glu635Gln	missense	Exon 12 of 21	ENSP00000489888.2	A0A1B0GTY3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1427968 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 707540

African (AFR) AF: 0.00 AC: 0 AN: 32614

American (AMR) AF: 0.00 AC: 0 AN: 40888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25498

East Asian (EAS) AF: 0.00 AC: 0 AN: 37476

South Asian (SAS) AF: 0.00 AC: 0 AN: 81170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096918

Other (OTH) AF: 0.00 AC: 0 AN: 59128

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.81
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.35
Sift	Benign	0.053	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.21
MutPred		0.51		Loss of stability (P = 0.0377)
MVP		0.71
MPC		0.63
ClinPred		0.65	D
GERP RS		3.8
Varity_R		0.18
gMVP		0.66
Mutation Taster		=87/13	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: rs371099308; hg19: chr5-178564818;