chr5-179125184-C-T

Position:

• chr5-179125184-C-T

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004534
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.20

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 353099.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.2751-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.2256-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047273851.1
ADAMTS2	XM_047417896.1	c.1869-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2751-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014244.5	ENSP00000251582	P2
ADAMTS2	ENST00000518335.3	c.2751-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1	c.2751-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000514008

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

GnomAD3 exomes AF: 0.00284 AC: 704 AN: 248240 Hom.: 2 AF XY: 0.00280 AC XY: 377 AN XY: 134674

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 SAS exome AF: 0.000131

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

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00504

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00321

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

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00455 Hom.: 1

Bravo AF: 0.00283

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ADAMTS2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2017	- -

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.5
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs112155474; hg19: chr5-178552185;