NM_014244.5:c.1630-3878T>C

Variant names:

• chr5-179143913-A-G
• rs10039254
• NM_014244.5:c.1630-3878T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014244.5(ADAMTS2):​c.1630-3878T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 152,014 control chromosomes in the GnomAD database, including 11,780 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (11780 hom., cov: 33)
• Consequence: ADAMTS2 NM_014244.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.297
• Publications: 11 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), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1630-3878T>C		intron_variant	Intron 10 of 21	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1135-3878T>C		intron_variant	Intron 9 of 20		XP_047273851.1
ADAMTS2	XM_047417896.1	c.748-3878T>C		intron_variant	Intron 8 of 19		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1630-3878T>C		intron_variant	Intron 10 of 21	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.1630-3878T>C		intron_variant	Intron 10 of 20	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.1630-3878T>C		intron_variant	Intron 10 of 20			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59384 AN: 151894 Hom.: 11769 Cov.: 33

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.355

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.391 AC: 59434 AN: 152014 Hom.: 11780 Cov.: 33 AF XY: 0.388 AC XY: 28860 AN XY: 74330

African (AFR) AF: 0.454 AC: 18809 AN: 41472

American (AMR) AF: 0.340 AC: 5191 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1466 AN: 3468

East Asian (EAS) AF: 0.237 AC: 1224 AN: 5170

South Asian (SAS) AF: 0.332 AC: 1601 AN: 4820

European-Finnish (FIN) AF: 0.364 AC: 3843 AN: 10560

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26207 AN: 67958

Other (OTH) AF: 0.353 AC: 744 AN: 2110

Alfa AF: 0.383 Hom.: 30915

Bravo AF: 0.390

Asia WGS AF: 0.259 AC: 901 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.1
DANN	Benign	0.32
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs10039254; hg19: chr5-178570914; COSMIC: COSV52369409;