rs162502

Positions:

• chr21-26960687-C-T
• chr21-26960687-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007038.5(ADAMTS5):​c.1104+4601G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,164 control chromosomes in the GnomAD database, including 4,294 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4294 hom., cov: 33)
• Consequence: ADAMTS5 NM_007038.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.266

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS5	NM_007038.5	c.1104+4601G>A		intron_variant		ENST00000284987.6	NP_008969.2
ADAMTS5	XM_047440680.1	c.1104+4601G>A		intron_variant			XP_047296636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS5	ENST00000284987.6	c.1104+4601G>A		intron_variant		1	NM_007038.5	ENSP00000284987.5
ADAMTS5	ENST00000652031.1	n.285+4601G>A		intron_variant				ENSP00000498989.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31674 AN: 152046 Hom.: 4288 Cov.: 33

Gnomad AFR AF: 0.0636

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.208

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.208 AC: 31687 AN: 152164 Hom.: 4294 Cov.: 33 AF XY: 0.216 AC XY: 16032 AN XY: 74364

Gnomad4 AFR AF: 0.0634

Gnomad4 AMR AF: 0.314

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.216

Alfa AF: 0.224 Hom.: 520

Bravo AF: 0.207

Asia WGS AF: 0.438 AC: 1517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.65

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: rs162502; hg19: chr21-28333006;