5-179154123-C-T

Position:

• chr5-179154123-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014244.5(ADAMTS2):​c.1308G>A​(p.Ala436Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,594,590 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (14 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.54

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 5-179154123-C-T is Benign according to our data. Variant chr5-179154123-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 353123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179154123-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00297 (452/152294) while in subpopulation NFE AF= 0.00402 (273/67986). AF 95% confidence interval is 0.00362. There are 2 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1308G>A	p.Ala436Ala	synonymous_variant	8/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.1308G>A	p.Ala436Ala	synonymous_variant	8/11		NP_067610.1
ADAMTS2	XM_047417895.1	c.813G>A	p.Ala271Ala	synonymous_variant	7/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.426G>A	p.Ala142Ala	synonymous_variant	6/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1308G>A	p.Ala436Ala	synonymous_variant	8/22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.1308G>A	p.Ala436Ala	synonymous_variant	8/11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.1308G>A	p.Ala436Ala	synonymous_variant	8/21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.1308G>A		non_coding_transcript_exon_variant	8/21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00402

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00257 AC: 545 AN: 212342 Hom.: 2 AF XY: 0.00251 AC XY: 292 AN XY: 116146

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00234

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000835

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00314 AC: 4535 AN: 1442296 Hom.: 14 Cov.: 32 AF XY: 0.00306 AC XY: 2191 AN XY: 716762

Gnomad4 AFR exome AF: 0.00345

Gnomad4 AMR exome AF: 0.000419

Gnomad4 ASJ exome AF: 0.00224

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000882

Gnomad4 FIN exome AF: 0.00398

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152294 Hom.: 2 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74476

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00402

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00269

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2022	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 02, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

ADAMTS2: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.8
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs41285549; hg19: chr5-178581124; COSMIC: COSV51103051;