rs113994124

chr9-133570346-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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 id is 696.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL2	NM_014694.4	c.2431G>A	p.Gly811Arg	missense_variant	17/19	ENST00000651351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL2	ENST00000651351.2	c.2431G>A	p.Gly811Arg	missense_variant	17/19		NM_014694.4	P1
ADAMTSL2	ENST00000393061.7	c.2758G>A	p.Gly920Arg	missense_variant	17/19	1
ADAMTSL2	ENST00000354484.8	c.2431G>A	p.Gly811Arg	missense_variant	17/19	1		P1
ADAMTSL2	ENST00000393060.1	c.2431G>A	p.Gly811Arg	missense_variant	17/19	1		P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.26e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Geleophysic dysplasia 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 26, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.9	H;.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.83
MutPred		0.93		Gain of MoRF binding (P = 0.0449);.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs113994124; hg19: chr9-136435468;