rs35462609

chr5-179181111-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014244.5(ADAMTS2):c.936C>T(p.Asn312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,766 control chromosomes in the GnomAD database, including 1,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (71 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1169 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.36

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=-0.5).
• BP6: Variant 5-179181111-G-A is Benign according to our data. Variant chr5-179181111-G-A is described in ClinVar as [Benign]. Clinvar id is 353128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179181111-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0264 (4011/152196) while in subpopulation NFE AF= 0.0401 (2724/67998). AF 95% confidence interval is 0.0388. There are 71 homozygotes in gnomad4. There are 1960 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 71 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.936C>T	p.Asn312=	synonymous_variant	5/22	ENST00000251582.12
ADAMTS2	NM_021599.4	c.936C>T	p.Asn312=	synonymous_variant	5/11
ADAMTS2	XM_047417895.1	c.441C>T	p.Asn147=	synonymous_variant	4/21
ADAMTS2	XM_047417896.1	c.54C>T	p.Asn18=	synonymous_variant	3/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.936C>T	p.Asn312=	synonymous_variant	5/22	1	NM_014244.5	P2
ADAMTS2	ENST00000274609.5	c.936C>T	p.Asn312=	synonymous_variant	5/11	1
ADAMTS2	ENST00000518335.3	c.936C>T	p.Asn312=	synonymous_variant	5/21	3		A2
ADAMTS2	ENST00000698889.1	c.936C>T	p.Asn312=	synonymous_variant, NMD_transcript_variant	5/21

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4011 AN: 152078 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.00688

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0268 AC: 6748 AN: 251326 Hom.: 152 AF XY: 0.0269 AC XY: 3652 AN XY: 135888

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00732

Gnomad FIN exome AF: 0.0603

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0362 AC: 52934 AN: 1461570 Hom.: 1169 Cov.: 31 AF XY: 0.0355 AC XY: 25797 AN XY: 727088

Gnomad4 AFR exome AF: 0.00565

Gnomad4 AMR exome AF: 0.0137

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00788

Gnomad4 FIN exome AF: 0.0566

Gnomad4 NFE exome AF: 0.0417

Gnomad4 OTH exome AF: 0.0303

GnomAD4 genome AF: 0.0264 AC: 4011 AN: 152196 Hom.: 71 Cov.: 32 AF XY: 0.0263 AC XY: 1960 AN XY: 74390

Gnomad4 AFR AF: 0.00686

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00602

Gnomad4 FIN AF: 0.0581

Gnomad4 NFE AF: 0.0401

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0350 Hom.: 74

Bravo AF: 0.0233

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0375

EpiControl AF: 0.0345

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, 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 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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 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. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	2.0
Dann	Benign	0.70

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: rs35462609; hg19: chr5-178608112;