rs780314895

Variant names:

• chr5-179122738-C-A
• rs780314895
• NM_014244.5:c.2994G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_014244.5(ADAMTS2):​c.2994G>T​(p.Arg998Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,553,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0350
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 5-179122738-C-A is Benign according to our data. Variant chr5-179122738-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469675.
• BP7: Synonymous conserved (PhyloP=-0.035 with no splicing effect.

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.2994G>T	p.Arg998Arg	synonymous	Exon 20 of 22	NP_055059.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.2994G>T	p.Arg998Arg	synonymous	Exon 20 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000957641.1		c.2937G>T	p.Arg979Arg	synonymous	Exon 20 of 22	ENSP00000627700.1
	ADAMTS2	ENST00000518335.3	TSL:3	c.2994G>T	p.Arg998Arg	synonymous	Exon 20 of 21	ENSP00000489888.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000629 AC: 10 AN: 159042 AF XY: 0.0000713

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 46 AN: 1401354 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 20 AN XY: 691506

African (AFR) AF: 0.00 AC: 0 AN: 31738

American (AMR) AF: 0.0000555 AC: 2 AN: 36018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35930

South Asian (SAS) AF: 0.00 AC: 0 AN: 79392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000398 AC: 43 AN: 1080888

Other (OTH) AF: 0.0000172 AC: 1 AN: 58148

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000132

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Ehlers-Danlos syndrome, dermatosparaxis type (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		-0.035

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: rs780314895; hg19: chr5-178549739;