rs34424371

Variant names:

• chr5-179154150-G-A
• rs34424371
• NM_014244.5:c.1281C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014244.5(ADAMTS2):​c.1281C>T​(p.Asp427Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,578,486 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (151 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (165 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.335
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Illumina, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-179154150-G-A is Benign according to our data. Variant chr5-179154150-G-A is described in ClinVar as Benign. ClinVar VariationId is 198855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.335 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

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.1281C>T	p.Asp427Asp	synonymous	Exon 8 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.1281C>T	p.Asp427Asp	synonymous	Exon 8 of 11	NP_067610.1	O95450-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.1281C>T	p.Asp427Asp	synonymous	Exon 8 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.1281C>T	p.Asp427Asp	synonymous	Exon 8 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.1281C>T	p.Asp427Asp	synonymous	Exon 8 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3704 AN: 152184 Hom.: 149 Cov.: 33

Gnomad AFR AF: 0.0827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00707 AC: 1337 AN: 189034 AF XY: 0.00519

Gnomad AFR exome AF: 0.0842

Gnomad AMR exome AF: 0.00786

Gnomad ASJ exome AF: 0.000334

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00278 AC: 3966 AN: 1426184 Hom.: 165 Cov.: 32 AF XY: 0.00247 AC XY: 1748 AN XY: 707492

African (AFR) AF: 0.0884 AC: 2926 AN: 33092

American (AMR) AF: 0.00915 AC: 371 AN: 40546

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 38516

South Asian (SAS) AF: 0.000292 AC: 24 AN: 82134

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40362

Middle Eastern (MID) AF: 0.00560 AC: 32 AN: 5712

European-Non Finnish (NFE) AF: 0.000214 AC: 236 AN: 1100734

Other (OTH) AF: 0.00626 AC: 372 AN: 59450

GnomAD4 genome AF: 0.0244 AC: 3714 AN: 152302 Hom.: 151 Cov.: 33 AF XY: 0.0238 AC XY: 1775 AN XY: 74480

African (AFR) AF: 0.0827 AC: 3435 AN: 41554

American (AMR) AF: 0.0137 AC: 209 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68004

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0132 Hom.: 24

Bravo AF: 0.0282

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Ehlers-Danlos syndrome, dermatosparaxis type (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.5
DANN	Benign	0.78
PhyloP100		0.34
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34424371; hg19: chr5-178581151;