chr21-26932893-C-T

Position:

• chr21-26932893-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1266 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16764 hom.)
• Consequence: ADAMTS5 NM_007038.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.57

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 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/exons	MANE	UniProt
ADAMTS5	NM_007038.5	c.1841G>A	p.Arg614His	missense_variant	5/8	ENST00000284987.6
ADAMTS5	XM_047440680.1	c.1673G>A	p.Arg558His	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS5	ENST00000284987.6	c.1841G>A	p.Arg614His	missense_variant	5/8	1	NM_007038.5	P1
	ENST00000426771.1	n.235-6723C>T		intron_variant, non_coding_transcript_variant		3
ADAMTS5	ENST00000652031.1	c.*572G>A		3_prime_UTR_variant, NMD_transcript_variant	6/9

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18778 AN: 151978 Hom.: 1268 Cov.: 32

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

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.: 32 AF XY: 0.146 AC XY: 105755 AN XY: 726780

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.: 32 AF XY: 0.122 AC XY: 9079 AN XY: 74342

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	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	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.5e-8	P
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.071	T
Polyphen		1.0	D
Vest4		0.27
MPC		1.5
ClinPred		0.025	T
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

Other links and lift over

dbSNP: rs2830585; hg19: chr21-28305212; COSMIC: COSV53175235;