5-179126018-T-C

Position:

• chr5-179126018-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014244.5(ADAMTS2):​c.2730A>G​(p.Pro910Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,613,404 control chromosomes in the GnomAD database, including 684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (366 hom., cov: 34)
  • Exomes 𝑓: 0.0038 (318 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.02

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-179126018-T-C is Benign according to our data. Variant chr5-179126018-T-C is described in ClinVar as [Benign]. Clinvar id is 353100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179126018-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.2730A>G	p.Pro910Pro	synonymous_variant	18/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.2235A>G	p.Pro745Pro	synonymous_variant	17/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.1848A>G	p.Pro616Pro	synonymous_variant	16/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2730A>G	p.Pro910Pro	synonymous_variant	18/22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.2730A>G	p.Pro910Pro	synonymous_variant	18/21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.2730A>G		non_coding_transcript_exon_variant	18/21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5522 AN: 152212 Hom.: 358 Cov.: 34

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.00941 AC: 2360 AN: 250720 Hom.: 128 AF XY: 0.00692 AC XY: 940 AN XY: 135776

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.00593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00378 AC: 5525 AN: 1461074 Hom.: 318 Cov.: 32 AF XY: 0.00321 AC XY: 2331 AN XY: 726838

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.00707

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.00846

GnomAD4 genome AF: 0.0365 AC: 5567 AN: 152330 Hom.: 366 Cov.: 34 AF XY: 0.0351 AC XY: 2616 AN XY: 74484

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0187 Hom.: 115

Bravo AF: 0.0411

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2020	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.063
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs6869261; hg19: chr5-178553019;