NM_007038.5:c.2075T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.69

Publications

45 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ADAMTS5	NM_007038.5 link	c.2075T>C	p.Leu692Pro	missense_variant	Exon 7 of 8	ENST00000284987.6	NP_008969.2	Q9UNA0
ADAMTS5	XM_047440680.1 link	c.1907T>C	p.Leu636Pro	missense_variant	Exon 6 of 7		XP_047296636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS5	ENST00000284987.6 link	c.2075T>C	p.Leu692Pro	missense_variant	Exon 7 of 8	1	NM_007038.5	ENSP00000284987.5	Q9UNA0
ADAMTS5	ENST00000652031.1 link	n.*806T>C		non_coding_transcript_exon_variant	Exon 8 of 9			ENSP00000498989.1	A0A494C1E4
ADAMTS5	ENST00000652031.1 link	n.*806T>C		3_prime_UTR_variant	Exon 8 of 9			ENSP00000498989.1	A0A494C1E4
ENSG00000223563	ENST00000426771.1 link	n.235-9580A>G		intron_variant	Intron 2 of 2	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

GnomAD2 exomes

AF:

0.829

AC:

208200

AN:

251044

AF XY:

0.838

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 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

African (AFR)

AF:

0.970

AC:

32469

AN:

33474

American (AMR)

AF:

0.696

AC:

31105

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

22932

AN:

26132

East Asian (EAS)

AF:

0.462

AC:

18356

AN:

39698

South Asian (SAS)

AF:

0.866

AC:

74693

AN:

86256

European-Finnish (FIN)

AF:

0.844

AC:

45100

AN:

53412

Middle Eastern (MID)

AF:

0.894

AC:

5154

AN:

5768

European-Non Finnish (NFE)

AF:

0.896

AC:

995973

AN:

1111912

Other (OTH)

AF:

0.865

AC:

52258

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

7944

15888

23832

31776

39720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21298

42596

63894

85192

106490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.885

AC:

134740

AN:

152182

Hom.:

60287

Cov.:

AF XY:

0.879

AC XY:

65346

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.963

AC:

39999

AN:

41554

American (AMR)

AF:

0.804

AC:

12295

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.882

AC:

3060

AN:

3468

East Asian (EAS)

AF:

0.487

AC:

2509

AN:

5152

South Asian (SAS)

AF:

0.872

AC:

4199

AN:

4816

European-Finnish (FIN)

AF:

0.845

AC:

8950

AN:

10592

Middle Eastern (MID)

AF:

0.939

AC:

276

AN:

294

European-Non Finnish (NFE)

AF:

0.894

AC:

60765

AN:

67988

Other (OTH)

AF:

0.876

AC:

1849

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

737

1473

2210

2946

3683

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.881

Hom.:

269974

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

Feb 23, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28081267) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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

PhyloP100

7.7

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

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over