rs113994124

Variant names:

• chr9-133570346-G-A
• rs113994124
• NM_014694.4:c.2431G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_014694.4(ADAMTSL2):​c.2431G>A​(p.Gly811Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,830 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ADAMTSL2 NM_014694.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.53
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-133570346-G-A is Pathogenic according to our data. Variant chr9-133570346-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 696.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	NM_014694.4	MANE Select	c.2431G>A	p.Gly811Arg	missense	Exon 17 of 19	NP_055509.2
	ADAMTSL2	NM_001145320.2		c.2431G>A	p.Gly811Arg	missense	Exon 17 of 19	NP_001138792.1	Q86TH1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL2	ENST00000651351.2	MANE Select	c.2431G>A	p.Gly811Arg	missense	Exon 17 of 19	ENSP00000498961.2	Q86TH1
	ADAMTSL2	ENST00000393061.7	TSL:1	c.2758G>A	p.Gly920Arg	missense	Exon 17 of 19	ENSP00000376781.3	B1B0D4
	ADAMTSL2	ENST00000354484.8	TSL:1	c.2431G>A	p.Gly811Arg	missense	Exon 17 of 19	ENSP00000346478.4	Q86TH1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394830 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688402

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35768

South Asian (SAS) AF: 0.00 AC: 0 AN: 79278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4730

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079394

Other (OTH) AF: 0.00 AC: 0 AN: 57878

GnomAD4 genome Cov.: 33

Alfa AF: 0.000380 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Geleophysic dysplasia 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.93		Gain of MoRF binding (P = 0.0449)
MVP		0.93
MPC		1.4
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.76
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.54		Position offset: 2

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

Other links and lift over

dbSNP: rs113994124; hg19: chr9-136435468;