rs407818

Variant names:

• chr5-179281208-A-T
• rs407818
• NM_014244.5:c.535-8144T>A

Variant summary

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

The NM_014244.5(ADAMTS2):​c.535-8144T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 152,130 control chromosomes in the GnomAD database, including 12,141 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 0.38 (12141 hom., cov: 33)
• Consequence: ADAMTS2 NM_014244.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 2 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.535-8144T>A		intron_variant	Intron 2 of 21	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.535-8144T>A		intron_variant	Intron 2 of 10		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.535-8144T>A		intron_variant	Intron 2 of 21	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.535-8144T>A		intron_variant	Intron 2 of 10	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.535-8144T>A		intron_variant	Intron 2 of 20	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.535-8144T>A		intron_variant	Intron 2 of 20			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57017 AN: 152010 Hom.: 12131 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.375 AC: 57052 AN: 152130 Hom.: 12141 Cov.: 33 AF XY: 0.377 AC XY: 28075 AN XY: 74376

African (AFR) AF: 0.152 AC: 6304 AN: 41532

American (AMR) AF: 0.398 AC: 6088 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1619 AN: 3470

East Asian (EAS) AF: 0.455 AC: 2352 AN: 5172

South Asian (SAS) AF: 0.490 AC: 2363 AN: 4822

European-Finnish (FIN) AF: 0.464 AC: 4906 AN: 10568

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.472 AC: 32102 AN: 67966

Other (OTH) AF: 0.388 AC: 819 AN: 2110

Alfa AF: 0.416 Hom.: 1975

Bravo AF: 0.357

Asia WGS AF: 0.431 AC: 1496 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.0
DANN	Benign	0.87
PhyloP100		1.7
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: rs407818; hg19: chr5-178708209;