21-26929935-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_007038.5(ADAMTS5):​c.2176G>A​(p.Gly726Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ADAMTS5
NM_007038.5 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS5NM_007038.5 linkc.2176G>A p.Gly726Arg missense_variant Exon 7 of 8 ENST00000284987.6 NP_008969.2 Q9UNA0
ADAMTS5XM_047440680.1 linkc.2008G>A p.Gly670Arg missense_variant Exon 6 of 7 XP_047296636.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS5ENST00000284987.6 linkc.2176G>A p.Gly726Arg missense_variant Exon 7 of 8 1 NM_007038.5 ENSP00000284987.5 Q9UNA0
ADAMTS5ENST00000652031.1 linkn.*907G>A non_coding_transcript_exon_variant Exon 8 of 9 ENSP00000498989.1 A0A494C1E4
ADAMTS5ENST00000652031.1 linkn.*907G>A 3_prime_UTR_variant Exon 8 of 9 ENSP00000498989.1 A0A494C1E4
ENSG00000223563ENST00000426771.1 linkn.235-9681C>T intron_variant Intron 2 of 2 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152102
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461802
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Premature ovarian failure Uncertain:1
Mar 02, 2020
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.7
D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.85
Gain of MoRF binding (P = 0.0652);
MVP
0.94
MPC
1.3
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.91
gMVP
0.97

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.

Other links and lift over

dbSNP: rs1986874557; hg19: chr21-28302254; API