rs546361762

Positions:

chr5-179125039-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -5.44

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
ADAMTS2	NM_014244.5 linkuse as main transcript	c.2892C>T	p.Pro964=	synonymous_variant	19/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.2397C>T	p.Pro799=	synonymous_variant	18/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.2010C>T	p.Pro670=	synonymous_variant	17/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.2892C>T	p.Pro964=	synonymous_variant	19/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.2892C>T	p.Pro964=	synonymous_variant	19/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.2892C>T	p.Pro964=	synonymous_variant, NMD_transcript_variant	19/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

133348

Hom.:

Cov.:

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:

AN:

238644

Hom.:

AF XY:

0.000115

AC XY:

AN XY:

129924

show subpopulations

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.:

Cov.:

AF XY:

0.0000971

AC XY:

AN XY:

720592

show subpopulations

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:

AN:

133398

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

AN XY:

64948

show subpopulations

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.:

EpiCase

AF:

0.000111

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Uncertain:1Benign: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	Labcorp Genetics (formerly Invitae), Labcorp	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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over