chr21-26930035-C-T

Variant names:

• chr21-26930035-C-T
• rs78795703
• NM_007038.5:c.2076G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007038.5(ADAMTS5):​c.2076G>A​(p.Leu692Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,926 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (12 hom.)
• Consequence: ADAMTS5 NM_007038.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.85
• Publications: 4 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]

ENSG00000223563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 21-26930035-C-T is Benign according to our data. Variant chr21-26930035-C-T is described in ClinVar as Benign. ClinVar VariationId is 781593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00637 (969/152132) while in subpopulation AFR AF = 0.0224 (931/41528). AF 95% confidence interval is 0.0212. There are 11 homozygotes in GnomAd4. There are 440 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 969 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS5	NM_007038.5	MANE Select	c.2076G>A	p.Leu692Leu	synonymous	Exon 7 of 8	NP_008969.2	Q9UNA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS5	ENST00000284987.6	TSL:1 MANE Select	c.2076G>A	p.Leu692Leu	synonymous	Exon 7 of 8	ENSP00000284987.5	Q9UNA0
	ADAMTS5	ENST00000970346.1		c.1908G>A	p.Leu636Leu	synonymous	Exon 6 of 7	ENSP00000640405.1
	ADAMTS5	ENST00000652031.1		n.*807G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000498989.1	A0A494C1E4

Frequencies

GnomAD3 genomes AF: 0.00635 AC: 966 AN: 152014 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00170 AC: 426 AN: 251052 AF XY: 0.00122

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000631 AC: 923 AN: 1461794 Hom.: 12 Cov.: 30 AF XY: 0.000539 AC XY: 392 AN XY: 727208

African (AFR) AF: 0.0218 AC: 731 AN: 33476

American (AMR) AF: 0.000962 AC: 43 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111938

Other (OTH) AF: 0.00116 AC: 70 AN: 60392

GnomAD4 genome AF: 0.00637 AC: 969 AN: 152132 Hom.: 11 Cov.: 32 AF XY: 0.00592 AC XY: 440 AN XY: 74378

African (AFR) AF: 0.0224 AC: 931 AN: 41528

American (AMR) AF: 0.00163 AC: 25 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67928

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00679

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0020
DANN	Benign	0.79
PhyloP100		-6.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78795703; hg19: chr21-28302354; COSMIC: COSV53178015;