21-26930036-A-G

Position:

chr21-26930036-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.89 ( 60287 hom., cov: 32)

Exomes 𝑓: 0.87 ( 564140 hom. )

Consequence

ADAMTS5
NM_007038.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.69

Variant links:

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]

ADAMTS5 links:

ENSG00000223563 (HGNC:):

ENSG00000223563 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ADAMTS5	NM_007038.5 link	c.2075T>C	p.Leu692Pro	missense_variant	7/8	ENST00000284987.6	NP_008969.2	Q9UNA0
ADAMTS5	XM_047440680.1 link	c.1907T>C	p.Leu636Pro	missense_variant	6/7		XP_047296636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADAMTS5	ENST00000284987.6 link	c.2075T>C	p.Leu692Pro	missense_variant	7/8	1	NM_007038.5	ENSP00000284987.5	Q9UNA0
ADAMTS5	ENST00000652031.1 link	n.*806T>C		non_coding_transcript_exon_variant	8/9			ENSP00000498989.1	A0A494C1E4
ADAMTS5	ENST00000652031.1 link	n.*806T>C		3_prime_UTR_variant	8/9			ENSP00000498989.1	A0A494C1E4
ENSG00000223563	ENST00000426771.1 link	n.235-9580A>G		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.885

AC:

134632

AN:

152064

Hom.:

60237

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.874

AC XY:

635903

AN XY:

727194

show subpopulations

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.:

AF XY:

0.879

AC XY:

65346

AN XY:

74378

show subpopulations

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

LINK: link

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

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.076

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0000025

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.7

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

9.3

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.074

MPC

0.72

ClinPred

0.016

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over