5-179152133-C-T

Variant names:

• chr5-179152133-C-T
• rs115550684
• NM_014244.5:c.1629+9G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, dermatosparaxis type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 281712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.1629+9G>A		intron	N/A	NP_055059.2
	ADAMTS2	NM_021599.4		c.1629+9G>A		intron	N/A	NP_067610.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1629+9G>A		intron	N/A	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.1629+9G>A		intron	N/A	ENSP00000274609.5
	ADAMTS2	ENST00000957641.1		c.1629+9G>A		intron	N/A	ENSP00000627700.1

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

GnomAD2 exomes AF: 0.00791 AC: 1986 AN: 251094 AF XY: 0.00898

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 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

African (AFR) AF: 0.00117 AC: 39 AN: 33378

American (AMR) AF: 0.00463 AC: 207 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00732 AC: 191 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0227 AC: 1958 AN: 86156

European-Finnish (FIN) AF: 0.00617 AC: 329 AN: 53330

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5752

European-Non Finnish (NFE) AF: 0.00783 AC: 8684 AN: 1108658

Other (OTH) AF: 0.00841 AC: 507 AN: 60276

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

African (AFR) AF: 0.00147 AC: 61 AN: 41568

American (AMR) AF: 0.00496 AC: 76 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4824

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00870 AC: 592 AN: 68008

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00594 Hom.: 0

Bravo AF: 0.00531

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Ehlers-Danlos syndrome, dermatosparaxis type (4)
-	-	2	not specified (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	15
DANN	Benign	0.53
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115550684; hg19: chr5-178579134;