5-179343878-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The ENST00000251582.12(ADAMTS2):​c.423C>G​(p.Gly141Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G141G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000047 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS2 ENST00000251582.12 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=-0.669 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000251582.12. 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>G	p.Gly141Gly	synonymous	Exon 2 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.423C>G	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>G	p.Gly141Gly	synonymous	Exon 2 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.423C>G	p.Gly141Gly	synonymous	Exon 2 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000518335.3	TSL:3	c.423C>G	p.Gly141Gly	synonymous	Exon 2 of 21	ENSP00000489888.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.000294 AC: 57 AN: 194052 AF XY: 0.000273

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.000686

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000283

Gnomad FIN exome AF: 0.000115

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000467 AC: 67 AN: 1434750 Hom.: 0 Cov.: 75 AF XY: 0.0000548 AC XY: 39 AN XY: 711594

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.000798 AC: 31 AN: 38836

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

East Asian (EAS) AF: 0.000158 AC: 6 AN: 38014

South Asian (SAS) AF: 0.0000361 AC: 3 AN: 83080

European-Finnish (FIN) AF: 0.000161 AC: 8 AN: 49602

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

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1101606

Other (OTH) AF: 0.0000337 AC: 2 AN: 59400

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.4
DANN	Benign	0.76
PhyloP100		-0.67

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: rs755099137; hg19: chr5-178770879;