5-179125184-C-T

Variant names:

• chr5-179125184-C-T
• rs112155474
• NM_014244.5:c.2751-4G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014244.5(ADAMTS2):​c.2751-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,612,074 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (25 hom.)
• Consequence: ADAMTS2 NM_014244.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004534
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.20
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-179125184-C-T is Benign according to our data. Variant chr5-179125184-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 353099.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00307 (468/152350) while in subpopulation NFE AF = 0.00522 (355/68028). AF 95% confidence interval is 0.00477. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 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.2751-4G>A		splice_region intron	N/A	NP_055059.2	O95450-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.2751-4G>A		splice_region intron	N/A	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000957641.1		c.2694-4G>A		splice_region intron	N/A	ENSP00000627700.1
	ADAMTS2	ENST00000518335.3	TSL:3	c.2751-4G>A		splice_region intron	N/A	ENSP00000489888.2	A0A1B0GTY3

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00284 AC: 704 AN: 248240 AF XY: 0.00280

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00519

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00585

Gnomad NFE exome AF: 0.00414

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00444 AC: 6484 AN: 1459724 Hom.: 25 Cov.: 37 AF XY: 0.00437 AC XY: 3177 AN XY: 726264

African (AFR) AF: 0.000866 AC: 29 AN: 33474

American (AMR) AF: 0.000939 AC: 42 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 140 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86246

European-Finnish (FIN) AF: 0.00504 AC: 260 AN: 51570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00521 AC: 5796 AN: 1111792

Other (OTH) AF: 0.00321 AC: 194 AN: 60354

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00273 AC XY: 203 AN XY: 74492

African (AFR) AF: 0.000769 AC: 32 AN: 41588

American (AMR) AF: 0.00150 AC: 23 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00522 AC: 355 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00464 Hom.: 1

Bravo AF: 0.00283

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Ehlers-Danlos syndrome, dermatosparaxis type (3)
-	1	2	not provided (3)
-	-	1	Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.5
DANN	Benign	0.67
PhyloP100		-1.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0
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: rs112155474; hg19: chr5-178552185;