rs387907064
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_014694.4(ADAMTSL2):c.215G>A(p.Arg72Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,350,642 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: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000017 ( 0 hom. )
Consequence
ADAMTSL2
NM_014694.4 missense
NM_014694.4 missense
Scores
11
5
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a domain TSP type-1 1 (size 59) in uniprot entity ATL2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_014694.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.895
PP5
?
Variant 9-133537529-G-A is Pathogenic according to our data. Variant chr9-133537529-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30944.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-133537529-G-A is described in Lovd as [Likely_pathogenic]. Variant chr9-133537529-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAMTSL2 | NM_014694.4 | c.215G>A | p.Arg72Gln | missense_variant | 3/19 | ENST00000651351.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAMTSL2 | ENST00000651351.2 | c.215G>A | p.Arg72Gln | missense_variant | 3/19 | NM_014694.4 | P1 | ||
ADAMTSL2 | ENST00000393061.7 | c.542G>A | p.Arg181Gln | missense_variant | 3/19 | 1 | |||
ADAMTSL2 | ENST00000354484.8 | c.215G>A | p.Arg72Gln | missense_variant | 3/19 | 1 | P1 | ||
ADAMTSL2 | ENST00000393060.1 | c.215G>A | p.Arg72Gln | missense_variant | 3/19 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 34
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GnomAD4 exome AF: 0.00000167 AC: 2AN: 1198420Hom.: 0 Cov.: 30 AF XY: 0.00000173 AC XY: 1AN XY: 577834
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74364
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Geleophysic dysplasia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0174);.;Loss of MoRF binding (P = 0.0174);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at