chr1-161193247-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005099.6(ADAMTS4):c.1877A>G(p.Gln626Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,613,388 control chromosomes in the GnomAD database, including 320,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.62 ( 30005 hom., cov: 32)

Exomes 𝑓: 0.63 ( 290652 hom. )

Consequence

ADAMTS4
NM_005099.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.140

Publications

54 publications found

Variant links:

Genes affected

ADAMTS4 (HGNC:220): (ADAM metallopeptidase with thrombospondin type 1 motif 4) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of this 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 enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAMTS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.153451E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005099.6. 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
	ADAMTS4	NM_005099.6	MANE Select	c.1877A>G	p.Gln626Arg	missense	Exon 7 of 9	NP_005090.3
	ADAMTS4	NM_001320336.3		c.1877A>G	p.Gln626Arg	missense	Exon 7 of 9	NP_001307265.1	O75173-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS4	ENST00000367996.6	TSL:1 MANE Select	c.1877A>G	p.Gln626Arg	missense	Exon 7 of 9	ENSP00000356975.4	O75173-1
ADAMTS4	ENST00000926274.1		c.1877A>G	p.Gln626Arg	missense	Exon 7 of 9	ENSP00000596333.1
ADAMTS4	ENST00000926273.1		c.1877A>G	p.Gln626Arg	missense	Exon 8 of 10	ENSP00000596332.1

Frequencies

GnomAD3 genomes

AF:

0.625

AC:

94879

AN:

151908

Hom.:

29962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.604

Gnomad AMI

AF:

0.611

Gnomad AMR

AF:

0.689

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.890

Gnomad SAS

AF:

0.749

Gnomad FIN

AF:

0.616

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.595

Gnomad OTH

AF:

0.631

GnomAD2 exomes

AF:

0.665

AC:

166295

AN:

249938

AF XY:

0.664

show subpopulations

Gnomad AFR exome

AF:

0.611

Gnomad AMR exome

AF:

0.777

Gnomad ASJ exome

AF:

0.612

Gnomad EAS exome

AF:

0.895

Gnomad FIN exome

AF:

0.606

Gnomad NFE exome

AF:

0.596

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

AF:

0.627

AC:

915809

AN:

1461362

Hom.:

290652

Cov.:

AF XY:

0.628

AC XY:

456613

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.618

AC:

20677

AN:

33480

American (AMR)

AF:

0.767

AC:

34270

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

16124

AN:

26118

East Asian (EAS)

AF:

0.920

AC:

36504

AN:

39696

South Asian (SAS)

AF:

0.741

AC:

63905

AN:

86240

European-Finnish (FIN)

AF:

0.601

AC:

32031

AN:

53260

Middle Eastern (MID)

AF:

0.641

AC:

3670

AN:

5724

European-Non Finnish (NFE)

AF:

0.603

AC:

669984

AN:

1111794

Other (OTH)

AF:

0.640

AC:

38644

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

19896

39792

59687

79583

99479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18480

36960

55440

73920

92400

<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:

0.625

AC:

94974

AN:

152026

Hom.:

30005

Cov.:

AF XY:

0.630

AC XY:

46806

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.605

AC:

25039

AN:

41420

American (AMR)

AF:

0.690

AC:

10546

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2130

AN:

3466

East Asian (EAS)

AF:

0.889

AC:

4603

AN:

5176

South Asian (SAS)

AF:

0.749

AC:

3610

AN:

4822

European-Finnish (FIN)

AF:

0.616

AC:

6517

AN:

10578

Middle Eastern (MID)

AF:

0.605

AC:

178

AN:

294

European-Non Finnish (NFE)

AF:

0.595

AC:

40454

AN:

67962

Other (OTH)

AF:

0.636

AC:

1341

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1799

3597

5396

7194

8993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.613

Hom.:

91873

Bravo

AF:

0.635

TwinsUK

AF:

0.607

AC:

2249

ALSPAC

AF:

0.598

AC:

2305

ESP6500AA

AF:

0.608

AC:

2678

ESP6500EA

AF:

0.600

AC:

5162

ExAC

AF:

0.660

AC:

80160

Asia WGS

AF:

0.821

AC:

2850

AN:

3478

EpiCase

AF:

0.598

EpiControl

AF:

0.595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.2

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.050

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.020

MetaRNN

Benign

6.2e-7

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.1

PhyloP100

0.14

PrimateAI

Benign

0.26

PROVEAN

Benign

1.6

REVEL

Benign

0.032

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.012

MPC

0.31

ClinPred

0.00066

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.36

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over