5-179128096-C-T

Position:

chr5-179128096-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014244.5(ADAMTS2):c.2480G>A(p.Arg827Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,613,704 control chromosomes in the GnomAD database, including 1,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 58 hom., cov: 32)

Exomes 𝑓: 0.033 ( 952 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.56

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005013287).

BP6

Variant 5-179128096-C-T is Benign according to our data. Variant chr5-179128096-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 353103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179128096-C-T is described in Lovd as [Benign]. Variant chr5-179128096-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3819/152218) while in subpopulation NFE AF= 0.0365 (2483/68010). AF 95% confidence interval is 0.0353. There are 58 homozygotes in gnomad4. There are 1772 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 linkuse as main transcript	c.2480G>A	p.Arg827Gln	missense_variant	17/22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.1985G>A	p.Arg662Gln	missense_variant	16/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.1598G>A	p.Arg533Gln	missense_variant	15/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.2480G>A	p.Arg827Gln	missense_variant	17/22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.2480G>A	p.Arg827Gln	missense_variant	17/21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 linkuse as main transcript	n.2480G>A		non_coding_transcript_exon_variant	17/21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3819

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00676

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0309

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0365

Gnomad OTH

AF:

0.0311

GnomAD3 exomes

AF:

0.0261

AC:

6551

AN:

251048

Hom.:

126

AF XY:

0.0263

AC XY:

3564

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.0198

Gnomad ASJ exome

AF:

0.0566

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00519

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0369

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0332

AC:

48523

AN:

1461486

Hom.:

952

Cov.:

AF XY:

0.0323

AC XY:

23480

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00562

Gnomad4 AMR exome

AF:

0.0212

Gnomad4 ASJ exome

AF:

0.0548

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00467

Gnomad4 FIN exome

AF:

0.0286

Gnomad4 NFE exome

AF:

0.0377

Gnomad4 OTH exome

AF:

0.0331

GnomAD4 genome

AF:

0.0251

AC:

3819

AN:

152218

Hom.:

Cov.:

AF XY:

0.0238

AC XY:

1772

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00674

Gnomad4 AMR

AF:

0.0256

Gnomad4 ASJ

AF:

0.0493

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0309

Gnomad4 NFE

AF:

0.0365

Gnomad4 OTH

AF:

0.0307

Alfa

AF:

0.0325

Hom.:

131

Bravo

AF:

0.0255

TwinsUK

AF:

0.0348

AC:

129

ALSPAC

AF:

0.0402

AC:

155

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0377

AC:

324

ExAC

AF:

0.0252

AC:

3064

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0444

EpiControl

AF:

0.0430

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2021	Variant summary: ADAMTS2 c.2480G>A (p.Arg827Gln) results in a conservative amino acid change located in the ADAM-TS Spacer 1 domain (IPR010294) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.026 in 251048 control chromosomes in the gnomAD database, including 126 homozygotes. The observed variant frequency is approximately 9- fold 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 benign. To our knowledge, there are no reports of of c.2480G>A in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating an impact on protein function published in the literature. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2016	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. -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.57

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.081

Sift

Benign

0.063

T;.

Sift4G

Benign

0.061

T;.

Polyphen

0.038

B;.

Vest4

0.10

MPC

0.48

ClinPred

0.021

GERP RS

3.4

Varity_R

0.14

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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