rs229052

chr21-26943889-G-Achr21-26943889-G-C

Variant summary

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

The NM_007038.5(ADAMTS5):c.1238-342C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 151,994 control chromosomes in the GnomAD database, including 38,124 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 0.70 (38124 hom., cov: 32)
• Consequence: ADAMTS5 NM_007038.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.257

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=-0.59).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS5	NM_007038.5	c.1238-342C>T		intron_variant		ENST00000284987.6
ADAMTS5	XM_047440680.1	c.1238-9140C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS5	ENST00000284987.6	c.1238-342C>T		intron_variant		1	NM_007038.5	P1
ADAMTS5	ENST00000652031.1	c.420-342C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106995 AN: 151878 Hom.: 38085 Cov.: 32

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.689

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

GnomAD4 genome AF: 0.705 AC: 107081 AN: 151994 Hom.: 38124 Cov.: 32 AF XY: 0.707 AC XY: 52505 AN XY: 74270

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.778

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.779

Gnomad4 SAS AF: 0.802

Gnomad4 FIN AF: 0.712

Gnomad4 NFE AF: 0.744

Gnomad4 OTH AF: 0.693

Alfa AF: 0.734 Hom.: 8356

Bravo AF: 0.702

Asia WGS AF: 0.789 AC: 2743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	8.8
Dann	Benign	0.83

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: rs229052; hg19: chr21-28316208;