chr19-8586198-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_030957.4(ADAMTS10):c.2584G>T(p.Ala862Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,611,990 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 237 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 198 hom. )

Consequence

ADAMTS10
NM_030957.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.17

Publications

8 publications found

Variant links:

Genes affected

ADAMTS10 (HGNC:13201): (ADAM metallopeptidase with thrombospondin type 1 motif 10) This gene belongs to the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin type-1 motifs) family of zinc-dependent proteases. ADAMTS proteases are complex secreted enzymes containing a prometalloprotease domain of the reprolysin type attached to an ancillary domain with a highly conserved structure that includes at least one thrombospondin type 1 repeat. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. The product of this gene plays a major role in growth and in skin, lens, and heart development. It is also a candidate gene for autosomal recessive Weill-Marchesani syndrome. [provided by RefSeq, Jul 2008]

ADAMTS10 Gene-Disease associations (from GenCC):

Weill-Marchesani syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Weill-Marchesani syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ADAMTS10 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=0.0016127229).

BP6

Variant 19-8586198-C-A is Benign according to our data. Variant chr19-8586198-C-A is described in ClinVar as Benign. ClinVar VariationId is 330582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030957.4. 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
	ADAMTS10	NM_030957.4	MANE Select	c.2584G>T	p.Ala862Ser	missense	Exon 22 of 26	NP_112219.3
	ADAMTS10	NM_001282352.2		c.1045G>T	p.Ala349Ser	missense	Exon 9 of 13	NP_001269281.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS10	ENST00000597188.6	TSL:5 MANE Select	c.2584G>T	p.Ala862Ser	missense	Exon 22 of 26	ENSP00000471851.1
ADAMTS10	ENST00000270328.8	TSL:5	c.2584G>T	p.Ala862Ser	missense	Exon 21 of 25	ENSP00000270328.4
ADAMTS10	ENST00000906412.1		c.2584G>T	p.Ala862Ser	missense	Exon 21 of 25	ENSP00000576471.1

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4587

AN:

152172

Hom.:

236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0139

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.00910

AC:

2256

AN:

247826

AF XY:

0.00719

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.00613

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.0134

Gnomad FIN exome

AF:

0.0000953

Gnomad NFE exome

AF:

0.000815

Gnomad OTH exome

AF:

0.00627

GnomAD4 exome

AF:

0.00341

AC:

4979

AN:

1459700

Hom.:

198

Cov.:

AF XY:

0.00311

AC XY:

2256

AN XY:

726178

show subpopulations

African (AFR)

AF:

0.102

AC:

3407

AN:

33440

American (AMR)

AF:

0.00669

AC:

299

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00169

AC:

AN:

26108

East Asian (EAS)

AF:

0.00635

AC:

252

AN:

39696

South Asian (SAS)

AF:

0.000406

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.0000761

AC:

AN:

52536

Middle Eastern (MID)

AF:

0.0179

AC:

AN:

4870

European-Non Finnish (NFE)

AF:

0.000321

AC:

357

AN:

1111906

Other (OTH)

AF:

0.00820

AC:

494

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

315

630

944

1259

1574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.0302

AC:

4599

AN:

152290

Hom.:

237

Cov.:

AF XY:

0.0300

AC XY:

2232

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.102

AC:

4232

AN:

41558

American (AMR)

AF:

0.0132

AC:

202

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0135

AC:

AN:

5176

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68018

Other (OTH)

AF:

0.0189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

220

440

660

880

1100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0167

Hom.:

Bravo

AF:

0.0348

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0949

AC:

418

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0103

AC:

1255

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.89

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

PhyloP100

2.2

PrimateAI

Benign

0.47

PROVEAN

Benign

0.88

REVEL

Benign

0.078

Sift

Benign

0.71

Sift4G

Benign

0.43

Vest4

0.073

MPC

1.3

ClinPred

0.0044

GERP RS

4.1

gMVP

0.27

Mutation Taster

=100/0

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