chr21-26943889-G-A

Variant names:

• chr21-26943889-G-A
• rs229052
• NM_007038.5:c.1238-342C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007038.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS5	NM_007038.5	MANE Select	c.1238-342C>T		intron	N/A	NP_008969.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS5	ENST00000284987.6	TSL:1 MANE Select	c.1238-342C>T		intron	N/A	ENSP00000284987.5
	ADAMTS5	ENST00000652031.1		n.419-342C>T		intron	N/A	ENSP00000498989.1

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

African (AFR) AF: 0.590 AC: 24455 AN: 41436

American (AMR) AF: 0.778 AC: 11874 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2556 AN: 3466

East Asian (EAS) AF: 0.779 AC: 4021 AN: 5160

South Asian (SAS) AF: 0.802 AC: 3867 AN: 4824

European-Finnish (FIN) AF: 0.712 AC: 7515 AN: 10558

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50576 AN: 67968

Other (OTH) AF: 0.693 AC: 1464 AN: 2114

Alfa AF: 0.731 Hom.: 8502

Bravo AF: 0.702

Asia WGS AF: 0.789 AC: 2743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.8
DANN	Benign	0.83
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs229052; hg19: chr21-28316208;