Genetic Variant ADAMTS10:c.435+24G>A (chr19-8604988-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_030957.4(ADAMTS10):c.435+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,571,508 control chromosomes in the GnomAD database, including 59,063 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4259 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54804 hom. )

Consequence

ADAMTS10
NM_030957.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.04

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS10	NM_030957.4 link	c.435+24G>A		intron_variant	Intron 4 of 25	ENST00000597188.6	NP_112219.3	Q9H324A0A0A0MQW6Q6ZN14Q59FE5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188.6 link	c.435+24G>A		intron_variant	Intron 4 of 25	5	NM_030957.4	ENSP00000471851.1		A0A0A0MQW6

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33714

AN:

152048

Hom.:

4262

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.0395

Gnomad SAS

AF:

0.0793

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.294

Gnomad OTH

AF:

0.245

GnomAD4 exome

AF:

0.267

AC:

379371

AN:

1419342

Hom.:

54804

Cov.:

AF XY:

0.263

AC XY:

184809

AN XY:

703214

show subpopulations

African (AFR)

AF:

0.122

AC:

3931

AN:

32144

American (AMR)

AF:

0.150

AC:

5711

AN:

37994

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

4782

AN:

25396

East Asian (EAS)

AF:

0.0353

AC:

1304

AN:

36926

South Asian (SAS)

AF:

0.0831

AC:

6790

AN:

81744

European-Finnish (FIN)

AF:

0.308

AC:

15418

AN:

50078

Middle Eastern (MID)

AF:

0.231

AC:

1323

AN:

5736

European-Non Finnish (NFE)

AF:

0.299

AC:

325631

AN:

1090494

Other (OTH)

AF:

0.246

AC:

14481

AN:

58830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

15498

30996

46494

61992

77490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10452

20904

31356

41808

52260

<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:

0.222

AC:

33706

AN:

152166

Hom.:

4259

Cov.:

AF XY:

0.218

AC XY:

16259

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.128

AC:

5308

AN:

41526

American (AMR)

AF:

0.195

AC:

2976

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

660

AN:

3470

East Asian (EAS)

AF:

0.0396

AC:

205

AN:

5180

South Asian (SAS)

AF:

0.0787

AC:

380

AN:

4826

European-Finnish (FIN)

AF:

0.306

AC:

3236

AN:

10592

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.294

AC:

19969

AN:

67984

Other (OTH)

AF:

0.243

AC:

514

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1319

2639

3958

5278

6597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.214

Hom.:

1104

Bravo

AF:

0.211

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.34

(source)

PhyloP100

-2.0

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over