chr21-26932893-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007038.5(ADAMTS5):c.1841G>A(p.Arg614His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,118 control chromosomes in the GnomAD database, including 18,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.12 ( 1266 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16764 hom. )

Consequence

ADAMTS5
NM_007038.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

ADAMTS5 (HGNC:221): (ADAM metallopeptidase with thrombospondin type 1 motif 5) 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 enzyme. This enzyme contains two C-terminal TS motifs and functions as an aggrecanase that cleaves aggrecan, a major proteoglycan of cartilage, and may mediate cartilage destruction in osteoarthritis. [provided by RefSeq, Feb 2016]

ADAMTS5 links:

ENSG00000223563 (HGNC:):

ENSG00000223563 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=0.0020451844).

BP6

Variant 21-26932893-C-T is Benign according to our data. Variant chr21-26932893-C-T is described in ClinVar as [Benign]. Clinvar id is 1181193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS5	NM_007038.5 link	c.1841G>A	p.Arg614His	missense_variant	Exon 5 of 8	ENST00000284987.6	NP_008969.2	Q9UNA0
ADAMTS5	XM_047440680.1 link	c.1673G>A	p.Arg558His	missense_variant	Exon 4 of 7		XP_047296636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS5	ENST00000284987.6 link	c.1841G>A	p.Arg614His	missense_variant	Exon 5 of 8	1	NM_007038.5	ENSP00000284987.5	Q9UNA0
ADAMTS5	ENST00000652031.1 link	n.*572G>A		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000498989.1	A0A494C1E4
ADAMTS5	ENST00000652031.1 link	n.*572G>A		3_prime_UTR_variant	Exon 6 of 9			ENSP00000498989.1	A0A494C1E4
ENSG00000223563	ENST00000426771.1 link	n.235-6723C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18778

AN:

151978

Hom.:

1268

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0686

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.0779

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.162

GnomAD3 exomes

AF:

0.125

AC:

31162

AN:

250042

Hom.:

2139

AF XY:

0.126

AC XY:

16990

AN XY:

135096

show subpopulations

Gnomad AFR exome

AF:

0.0638

Gnomad AMR exome

AF:

0.0824

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.0869

Gnomad SAS exome

AF:

0.0828

Gnomad FIN exome

AF:

0.150

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.147

AC:

214833

AN:

1461022

Hom.:

16764

Cov.:

AF XY:

0.146

AC XY:

105755

AN XY:

726780

show subpopulations

Gnomad4 AFR exome

AF:

0.0608

Gnomad4 AMR exome

AF:

0.0880

Gnomad4 ASJ exome

AF:

0.144

Gnomad4 EAS exome

AF:

0.130

Gnomad4 SAS exome

AF:

0.0804

Gnomad4 FIN exome

AF:

0.146

Gnomad4 NFE exome

AF:

0.158

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.123

AC:

18766

AN:

152096

Hom.:

1266

Cov.:

AF XY:

0.122

AC XY:

9079

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0684

Gnomad4 AMR

AF:

0.125

Gnomad4 ASJ

AF:

0.140

Gnomad4 EAS

AF:

0.114

Gnomad4 SAS

AF:

0.0773

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.160

Alfa

AF:

0.149

Hom.:

4481

Bravo

AF:

0.123

TwinsUK

AF:

0.163

AC:

603

ALSPAC

AF:

0.157

AC:

607

ESP6500AA

AF:

0.0724

AC:

319

ESP6500EA

AF:

0.160

AC:

1372

ExAC

AF:

0.125

AC:

15208

Asia WGS

AF:

0.0870

AC:

302

AN:

3478

EpiCase

AF:

0.158

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22961118) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Sift4G

Benign

0.071

Polyphen

1.0

Vest4

0.27

MPC

1.5

ClinPred

0.025

GERP RS

6.0

Varity_R

0.85

gMVP

0.62

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