rs61757478

Positions:

chr5-179153548-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000251582.12(ADAMTS2):c.1458C>T(p.Tyr486=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,610,818 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 23 hom. )

Consequence

ADAMTS2
ENST00000251582.12 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.79

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 5-179153548-G-A is Benign according to our data. Variant chr5-179153548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 353121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179153548-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.79 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0041 (624/152260) while in subpopulation NFE AF= 0.00553 (376/68002). AF 95% confidence interval is 0.00507. There are 4 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAMTS2	NM_014244.5 linkuse as main transcript	c.1458C>T	p.Tyr486=	synonymous_variant	9/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4 linkuse as main transcript	c.1458C>T	p.Tyr486=	synonymous_variant	9/11		NP_067610.1
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.963C>T	p.Tyr321=	synonymous_variant	8/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.576C>T	p.Tyr192=	synonymous_variant	7/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.1458C>T	p.Tyr486=	synonymous_variant	9/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.1458C>T	p.Tyr486=	synonymous_variant	9/11	1		ENSP00000274609		O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.1458C>T	p.Tyr486=	synonymous_variant	9/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.1458C>T	p.Tyr486=	synonymous_variant, NMD_transcript_variant	9/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

624

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00553

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00418

AC:

1032

AN:

246670

Hom.:

AF XY:

0.00409

AC XY:

548

AN XY:

133988

show subpopulations

Gnomad AFR exome

AF:

0.000499

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000983

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00416

AC:

6066

AN:

1458558

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

3029

AN XY:

725710

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000986

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.00431

Gnomad4 OTH exome

AF:

0.00378

GnomAD4 genome

AF:

0.00410

AC:

624

AN:

152260

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

331

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0178

Gnomad4 NFE

AF:

0.00553

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00501

Hom.:

Bravo

AF:

0.00253

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00380

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely 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 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 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ADAMTS2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 26, 2018

Variant summary: ADAMTS2 c.1458C>T alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0046 in 272964 control chromosomes, including 7 homozygotes (gnomAD). The observed variant frequency within Finnish control individuals (0.018) in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.1458C>T in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 classifying it as benign/likely benign and 1 as VUS). Based on the evidence outlined above, the variant was classified as benign. -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.4

DANN

Benign

0.66

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over