5-179152133-C-T

Position:

• chr5-179152133-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014244.5(ADAMTS2):​c.1629+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 1,610,288 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (91 hom.)
• Consequence: ADAMTS2 NM_014244.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.435

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-179152133-C-T is Benign according to our data. Variant chr5-179152133-C-T is described in ClinVar as [Benign]. Clinvar id is 281712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179152133-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00606 (923/152288) while in subpopulation SAS AF= 0.0172 (83/4824). AF 95% confidence interval is 0.0142. There are 3 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1629+9G>A		intron_variant		ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.1629+9G>A		intron_variant			NP_067610.1
ADAMTS2	XM_047417895.1	c.1134+9G>A		intron_variant			XP_047273851.1
ADAMTS2	XM_047417896.1	c.747+9G>A		intron_variant			XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1629+9G>A		intron_variant		1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.1629+9G>A		intron_variant		1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.1629+9G>A		intron_variant		3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.1629+9G>A		intron_variant				ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 925 AN: 152170 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00791 AC: 1986 AN: 251094 Hom.: 13 AF XY: 0.00898 AC XY: 1219 AN XY: 135756

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0222

Gnomad FIN exome AF: 0.00648

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00824 AC: 12013 AN: 1458000 Hom.: 91 Cov.: 31 AF XY: 0.00886 AC XY: 6427 AN XY: 725610

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00732

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.00617

Gnomad4 NFE exome AF: 0.00783

Gnomad4 OTH exome AF: 0.00841

GnomAD4 genome AF: 0.00606 AC: 923 AN: 152288 Hom.: 3 Cov.: 33 AF XY: 0.00598 AC XY: 445 AN XY: 74458

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00496

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00870

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00594 Hom.: 0

Bravo AF: 0.00531

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:4

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 11, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2020	Variant summary: ADAMTS2 c.1629+9G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0079 in 251094 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 2.74 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1629+9G>A in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign(n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2015	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 10, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	15
DANN	Benign	0.53

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: rs115550684; hg19: chr5-178579134;