NM_014244.5:c.423C>T

Variant names:

• chr5-179343878-G-A
• rs755099137
• NM_014244.5:c.423C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_014244.5(ADAMTS2):​c.423C>T​(p.Gly141Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000958 in 1,586,926 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 0.000092 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.669
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-179343878-G-A is Benign according to our data. Variant chr5-179343878-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 537400.
• BP7: Synonymous conserved (PhyloP=-0.669 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.423C>T	p.Gly141Gly	synonymous	Exon 2 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.423C>T	p.Gly141Gly	synonymous	Exon 2 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.423C>T	p.Gly141Gly	synonymous	Exon 2 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.423C>T	p.Gly141Gly	synonymous	Exon 2 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000957641.1		c.423C>T	p.Gly141Gly	synonymous	Exon 2 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152150 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000562 AC: 109 AN: 194052 AF XY: 0.000357

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000199

GnomAD4 exome AF: 0.0000962 AC: 138 AN: 1434776 Hom.: 0 Cov.: 75 AF XY: 0.0000745 AC XY: 53 AN XY: 711614

African (AFR) AF: 0.00 AC: 0 AN: 33038

American (AMR) AF: 0.00342 AC: 133 AN: 38840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.00 AC: 0 AN: 38018

South Asian (SAS) AF: 0.00 AC: 0 AN: 83080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101616

Other (OTH) AF: 0.0000842 AC: 5 AN: 59400

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152150 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.000850 AC: 13 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000264

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Ehlers-Danlos syndrome, dermatosparaxis type (2)
-	-	1	ADAMTS2-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.9
DANN	Benign	0.86
PhyloP100		-0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs755099137; hg19: chr5-178770879;