rs61731454

Positions:

• chr5-179140021-T-C

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.1644A>G​(p.Gly548=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,978 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (13 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0670

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=-0.53).
• BP6: Variant 5-179140021-T-C is Benign according to our data. Variant chr5-179140021-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 353120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.067 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00717 (1092/152248) while in subpopulation AFR AF= 0.0245 (1017/41544). AF 95% confidence interval is 0.0232. There are 17 homozygotes in gnomad4. There are 507 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1644A>G	p.Gly548=	synonymous_variant	11/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1149A>G	p.Gly383=	synonymous_variant	10/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.762A>G	p.Gly254=	synonymous_variant	9/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1644A>G	p.Gly548=	synonymous_variant	11/22	1	NM_014244.5	ENSP00000251582	P2
ADAMTS2	ENST00000518335.3	c.1644A>G	p.Gly548=	synonymous_variant	11/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1	c.1644A>G	p.Gly548=	synonymous_variant, NMD_transcript_variant	11/21			ENSP00000514008

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 1091 AN: 152130 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00191 AC: 480 AN: 251434 Hom.: 6 AF XY: 0.00141 AC XY: 191 AN XY: 135898

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000834 AC: 1219 AN: 1461730 Hom.: 13 Cov.: 31 AF XY: 0.000699 AC XY: 508 AN XY: 727170

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00717 AC: 1092 AN: 152248 Hom.: 17 Cov.: 32 AF XY: 0.00681 AC XY: 507 AN XY: 74452

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00288 Hom.: 1

Bravo AF: 0.00809

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.4
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs61731454; hg19: chr5-178567022;