rs137852555
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1PM1PM2PP3_ModeratePP5
The NM_000451.4(SHOX):c.458G>T(p.Arg153Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.
Frequency
Genomes: not found (cov: 32)
Consequence
SHOX
NM_000451.4 missense
NM_000451.4 missense
Scores
7
7
2
Clinical Significance
Conservation
PhyloP100: 8.09
Genes affected
SHOX (HGNC:10853): (SHOX homeobox) This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PS1
?
Transcript NM_000451.4 (SHOX) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 9876
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000451.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.928
PP5
?
Variant X-634798-G-T is Pathogenic according to our data. Variant chrX-634798-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 9876.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-634798-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHOX | NM_000451.4 | c.458G>T | p.Arg153Leu | missense_variant | 2/5 | ENST00000686671.1 | |
SHOX | NM_006883.2 | c.458G>T | p.Arg153Leu | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHOX | ENST00000686671.1 | c.458G>T | p.Arg153Leu | missense_variant | 2/5 | NM_000451.4 | P1 | ||
SHOX | ENST00000381575.6 | c.458G>T | p.Arg153Leu | missense_variant | 2/5 | 1 | |||
SHOX | ENST00000381578.6 | c.458G>T | p.Arg153Leu | missense_variant | 3/6 | 5 | P1 | ||
SHOX | ENST00000334060.8 | c.458G>T | p.Arg153Leu | missense_variant | 3/6 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Leri-Weill dyschondrosteosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L
MutationTaster
Benign
N;N;N;N;N;N
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0252);Loss of MoRF binding (P = 0.0252);Loss of MoRF binding (P = 0.0252);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at