9-133539799-G-A

Variant names:

• chr9-133539799-G-A
• rs113994122
• NM_014694.4:c.338G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014694.4(ADAMTSL2):​c.338G>A​(p.Arg113His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,398,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ADAMTSL2 NM_014694.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.42
• Publications: 8 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-133539799-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1326072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 9-133539799-G-A is Pathogenic according to our data. Variant chr9-133539799-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	NM_014694.4	MANE Select	c.338G>A	p.Arg113His	missense	Exon 5 of 19	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.338G>A	p.Arg113His	missense	Exon 5 of 19	NP_001138792.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	ENST00000651351.2	MANE Select	c.338G>A	p.Arg113His	missense	Exon 5 of 19	ENSP00000498961.2
	ADAMTSL2	ENST00000393061.7	TSL:1	c.665G>A	p.Arg222His	missense	Exon 5 of 19	ENSP00000376781.3
	ADAMTSL2	ENST00000354484.8	TSL:1	c.338G>A	p.Arg113His	missense	Exon 5 of 19	ENSP00000346478.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 155946 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1398256 Hom.: 0 Cov.: 33 AF XY: 0.00000435 AC XY: 3 AN XY: 689644

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.0000280 AC: 1 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 35706

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078682

Other (OTH) AF: 0.00 AC: 0 AN: 57960

GnomAD4 genome Cov.: 34

Alfa AF: 0.000668 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Geleophysic dysplasia 1 Pathogenic:2 Other:1

Mar 26, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lethal short-limb skeletal dysplasia, Al Gazali type Pathogenic:1

Oct 11, 2022

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.35	D
PhyloP100		7.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.83		Loss of phosphorylation at S111 (P = 0.0932)
MVP		0.91
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.49
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113994122; hg19: chr9-136404921;