chr21-26924092-C-A

Position:

• chr21-26924092-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007038.5(ADAMTS5):​c.2754G>T​(p.Arg918Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS5 NM_007038.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.287

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS5	NM_007038.5	c.2754G>T	p.Arg918Ser	missense_variant	8/8	ENST00000284987.6
ADAMTS5	XM_047440680.1	c.2586G>T	p.Arg862Ser	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS5	ENST00000284987.6	c.2754G>T	p.Arg918Ser	missense_variant	8/8	1	NM_007038.5	P1
	ENST00000426771.1	n.234+14062C>A		intron_variant, non_coding_transcript_variant		3
ADAMTS5	ENST00000652031.1	c.*1485G>T		3_prime_UTR_variant, NMD_transcript_variant	9/9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.2754G>T (p.R918S) alteration is located in exon 8 (coding exon 8) of the ADAMTS5 gene. This alteration results from a G to T substitution at nucleotide position 2754, causing the arginine (R) at amino acid position 918 to be replaced by a serine (S). 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	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.34		Loss of MoRF binding (P = 0.0444);
MVP		0.85
MPC		1.4
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.68
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-28296411;