rs546361762

chr5-179125039-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_014244.5(ADAMTS2):c.2892C>T(p.Pro964=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,448,296 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -5.44

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-179125039-G-A is Benign according to our data. Variant chr5-179125039-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 514658.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-5.44 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.2892C>T	p.Pro964=	synonymous_variant	19/22	ENST00000251582.12
ADAMTS2	XM_047417895.1	c.2397C>T	p.Pro799=	synonymous_variant	18/21
ADAMTS2	XM_047417896.1	c.2010C>T	p.Pro670=	synonymous_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2892C>T	p.Pro964=	synonymous_variant	19/22	1	NM_014244.5	P2
ADAMTS2	ENST00000518335.3	c.2892C>T	p.Pro964=	synonymous_variant	19/21	3		A2
ADAMTS2	ENST00000698889.1	c.2892C>T	p.Pro964=	synonymous_variant, NMD_transcript_variant	19/21

Frequencies

GnomAD3 genomes AF: 0.00 AC: 64 AN: 133348 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.000765

Gnomad AMI AF: 0.00259

Gnomad AMR AF: 0.000299

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000448

Gnomad SAS AF: 0.000483

Gnomad FIN AF: 0.000862

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000274

Gnomad OTH AF: 0.00165

GnomAD3 exomes AF: 0.000134 AC: 32 AN: 238644 Hom.: 0 AF XY: 0.000115 AC XY: 15 AN XY: 129924

Gnomad AFR exome AF: 0.000514

Gnomad AMR exome AF: 0.000418

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000581

Gnomad SAS exome AF: 0.0000695

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.0000640

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 170 AN: 1448296 Hom.: 1 Cov.: 38 AF XY: 0.0000971 AC XY: 70 AN XY: 720592

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000350

Gnomad4 ASJ exome AF: 0.0000779

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000185

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000480 AC: 64 AN: 133398 Hom.: 0 Cov.: 33 AF XY: 0.000477 AC XY: 31 AN XY: 64948

Gnomad4 AFR AF: 0.000764

Gnomad4 AMR AF: 0.000298

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000449

Gnomad4 SAS AF: 0.000484

Gnomad4 FIN AF: 0.000862

Gnomad4 NFE AF: 0.000274

Gnomad4 OTH AF: 0.00164

Alfa AF: 0.00174 Hom.: 0

EpiCase AF: 0.000111

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	2.5
Dann	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs546361762; hg19: chr5-178552040; COSMIC: COSV52382771; COSMIC: COSV52382771;