chr21-26953456-C-G

Position:

• chr21-26953456-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.1237+1283G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 151,990 control chromosomes in the GnomAD database, including 24,275 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 0.56 (24275 hom., cov: 32)
• Consequence: ADAMTS5 NM_007038.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.815

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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS5	NM_007038.5	c.1237+1283G>C		intron_variant		ENST00000284987.6	NP_008969.2
ADAMTS5	XM_047440680.1	c.1237+1283G>C		intron_variant			XP_047296636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS5	ENST00000284987.6	c.1237+1283G>C		intron_variant		1	NM_007038.5	ENSP00000284987	P1
ADAMTS5	ENST00000652031.1	c.419+1283G>C		intron_variant, NMD_transcript_variant				ENSP00000498989

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84735 AN: 151872 Hom.: 24264 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.554

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

GnomAD4 genome AF: 0.558 AC: 84777 AN: 151990 Hom.: 24275 Cov.: 32 AF XY: 0.560 AC XY: 41596 AN XY: 74294

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.669

Gnomad4 FIN AF: 0.626

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.552

Alfa AF: 0.485 Hom.: 1461

Bravo AF: 0.542

Asia WGS AF: 0.546 AC: 1901 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.51

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: rs162509; hg19: chr21-28325775;