chr9-133536800-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014694.4(ADAMTSL2):c.88A>G(p.Thr30Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,182 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T30M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 48 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 29 hom. )

Consequence

ADAMTSL2
NM_014694.4 missense, splice_region

Scores

Splicing: ADA: 0.00004065

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0760

Publications

1 publications found

Variant links:

Genes affected

ADAMTSL2 (HGNC:14631): (ADAMTS like 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and ADAMTS-like 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 protein encoded by this gene lacks the protease domain, and is therefore of a member of the the ADAMTS-like protein subfamily. It is a secreted glycoprotein that binds the cell surface and extracellular matrix; it also interacts with latent transforming growth factor beta binding protein 1. Mutations in this gene have been associated with geleophysic dysplasia. [provided by RefSeq, Feb 2009]

ADAMTSL2 Gene-Disease associations (from GenCC):

geleophysic dysplasia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Ehlers-Danlos syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ADAMTSL2 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=0.0027523935).

BP6

Variant 9-133536800-A-G is Benign according to our data. Variant chr9-133536800-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 235675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1804/152344) while in subpopulation AFR AF = 0.0416 (1730/41578). AF 95% confidence interval is 0.04. There are 48 homozygotes in GnomAd4. There are 872 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4 link	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	Exon 2 of 19	ENST00000651351.2	NP_055509.2	Q86TH1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTSL2	ENST00000651351.2 link	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	Exon 2 of 19		NM_014694.4	ENSP00000498961.2	Q86TH1
ADAMTSL2	ENST00000393061.7 link	c.415A>G	p.Thr139Ala	missense_variant, splice_region_variant	Exon 2 of 19	1		ENSP00000376781.3	B1B0D4
ADAMTSL2	ENST00000354484.8 link	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	Exon 2 of 19	1		ENSP00000346478.4	Q86TH1
ADAMTSL2	ENST00000393060.1 link	c.88A>G	p.Thr30Ala	missense_variant, splice_region_variant	Exon 2 of 19	1		ENSP00000376780.1	Q86TH1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1800

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0416

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00325

AC:

815

AN:

250590

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.0436

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00116

AC:

1697

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

755

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0407

AC:

1364

AN:

33480

American (AMR)

AF:

0.00233

AC:

104

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000782

AC:

AN:

1112006

Other (OTH)

AF:

0.00224

AC:

135

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

103

205

308

410

513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0118

AC:

1804

AN:

152344

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

872

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0416

AC:

1730

AN:

41578

American (AMR)

AF:

0.00327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00524

Hom.:

Bravo

AF:

0.0130

ESP6500AA

AF:

0.0415

AC:

183

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00404

AC:

490

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 21, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.9

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.012

T;T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.43

.;T;T

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-0.076

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.010

N;N;N

REVEL

Benign

0.026

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.82

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.066

MVP

0.50

MPC

0.42

ClinPred

0.0015

GERP RS

1.8

Varity_R

0.032

gMVP

0.40

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000041

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.16

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