21-26924148-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_007038.5(ADAMTS5):​c.2698G>A​(p.Val900Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,920 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 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ADAMTS5
NM_007038.5 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34
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_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.833
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAMTS5NM_007038.5 linkc.2698G>A p.Val900Met missense_variant Exon 8 of 8 ENST00000284987.6 NP_008969.2 Q9UNA0
ADAMTS5XM_047440680.1 linkc.2530G>A p.Val844Met missense_variant Exon 7 of 7 XP_047296636.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS5ENST00000284987.6 linkc.2698G>A p.Val900Met missense_variant Exon 8 of 8 1 NM_007038.5 ENSP00000284987.5 Q9UNA0
ADAMTS5ENST00000652031.1 linkn.*1429G>A non_coding_transcript_exon_variant Exon 9 of 9 ENSP00000498989.1 A0A494C1E4
ADAMTS5ENST00000652031.1 linkn.*1429G>A 3_prime_UTR_variant Exon 9 of 9 ENSP00000498989.1 A0A494C1E4
ENSG00000223563ENST00000426771.1 linkn.234+14118C>T intron_variant Intron 2 of 2 3

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251064
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135660
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461670
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727092
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 11, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2698G>A (p.V900M) alteration is located in exon 8 (coding exon 8) of the ADAMTS5 gene. This alteration results from a G to A substitution at nucleotide position 2698, causing the valine (V) at amino acid position 900 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Uncertain
0.057
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.47
T
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.053
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-2.7
D
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.75
MVP
0.72
MPC
1.3
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.68
gMVP
0.61

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: rs141206983; hg19: chr21-28296467; API