dbSNP rs1275168164: ADAMTS5:p.Gly810Arg (chr21-26924418-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007038.5(ADAMTS5):c.2428G>C(p.Gly810Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G810S) has been classified as Uncertain significance.

Frequency

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

Consequence

ADAMTS5
NM_007038.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.54

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS5	NM_007038.5 link	c.2428G>C	p.Gly810Arg	missense_variant	Exon 8 of 8	ENST00000284987.6	NP_008969.2	Q9UNA0
ADAMTS5	XM_047440680.1 link	c.2260G>C	p.Gly754Arg	missense_variant	Exon 7 of 7		XP_047296636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS5	ENST00000284987.6 link	c.2428G>C	p.Gly810Arg	missense_variant	Exon 8 of 8	1	NM_007038.5	ENSP00000284987.5	Q9UNA0
ADAMTS5	ENST00000652031.1 link	n.*1159G>C		non_coding_transcript_exon_variant	Exon 9 of 9			ENSP00000498989.1	A0A494C1E4
ADAMTS5	ENST00000652031.1 link	n.*1159G>C		3_prime_UTR_variant	Exon 9 of 9			ENSP00000498989.1	A0A494C1E4
ENSG00000223563	ENST00000426771.1 link	n.234+14388C>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.3

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.85

MutPred

0.71

Loss of catalytic residue at S812 (P = 0.0507);

MVP

0.83

MPC

1.4

ClinPred

1.0

GERP RS

5.8

Varity_R

0.86

gMVP

0.74

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over