chr21-26930036-A-G

Position:

• chr21-26930036-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007038.5(ADAMTS5):​c.2075T>C​(p.Leu692Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.875 in 1,613,948 control chromosomes in the GnomAD database, including 624,427 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. L692L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.89 (60287 hom., cov: 32)
  • Exomes 𝑓: 0.87 (564140 hom.)
• Consequence: ADAMTS5 NM_007038.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.69

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.499245E-6).
• BP6: Variant 21-26930036-A-G is Benign according to our data. Variant chr21-26930036-A-G is described in ClinVar as [Benign]. Clinvar id is 1249546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS5	NM_007038.5	c.2075T>C	p.Leu692Pro	missense_variant	7/8	ENST00000284987.6
ADAMTS5	XM_047440680.1	c.1907T>C	p.Leu636Pro	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS5	ENST00000284987.6	c.2075T>C	p.Leu692Pro	missense_variant	7/8	1	NM_007038.5	P1
	ENST00000426771.1	n.235-9580A>G		intron_variant, non_coding_transcript_variant		3
ADAMTS5	ENST00000652031.1	c.*806T>C		3_prime_UTR_variant, NMD_transcript_variant	8/9

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134632 AN: 152064 Hom.: 60237 Cov.: 32

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.894

Gnomad OTH AF: 0.877

GnomAD3 exomes AF: 0.829 AC: 208200 AN: 251044 Hom.: 88616 AF XY: 0.838 AC XY: 113617 AN XY: 135644

Gnomad AFR exome AF: 0.967

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.880

Gnomad EAS exome AF: 0.469

Gnomad SAS exome AF: 0.868

Gnomad FIN exome AF: 0.847

Gnomad NFE exome AF: 0.893

Gnomad OTH exome AF: 0.854

GnomAD4 exome AF: 0.874 AC: 1278040 AN: 1461766 Hom.: 564140 Cov.: 53 AF XY: 0.874 AC XY: 635903 AN XY: 727194

Gnomad4 AFR exome AF: 0.970

Gnomad4 AMR exome AF: 0.696

Gnomad4 ASJ exome AF: 0.878

Gnomad4 EAS exome AF: 0.462

Gnomad4 SAS exome AF: 0.866

Gnomad4 FIN exome AF: 0.844

Gnomad4 NFE exome AF: 0.896

Gnomad4 OTH exome AF: 0.865

GnomAD4 genome AF: 0.885 AC: 134740 AN: 152182 Hom.: 60287 Cov.: 32 AF XY: 0.879 AC XY: 65346 AN XY: 74378

Gnomad4 AFR AF: 0.963

Gnomad4 AMR AF: 0.804

Gnomad4 ASJ AF: 0.882

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.872

Gnomad4 FIN AF: 0.845

Gnomad4 NFE AF: 0.894

Gnomad4 OTH AF: 0.876

Alfa AF: 0.881 Hom.: 149167

Bravo AF: 0.879

TwinsUK AF: 0.900 AC: 3336

ALSPAC AF: 0.900 AC: 3469

ESP6500AA AF: 0.959 AC: 4227

ESP6500EA AF: 0.892 AC: 7670

ExAC AF: 0.840 AC: 101967

Asia WGS AF: 0.737 AC: 2568 AN: 3478

EpiCase AF: 0.894

EpiControl AF: 0.892

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 28081267) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.61
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	0.00099	P
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	9.3	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.72
ClinPred		0.016	T
GERP RS		6.0
Varity_R		0.20
gMVP		0.73

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: rs226794; hg19: chr21-28302355; COSMIC: COSV53179651;