chrX-630463-C-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_006883.2(SHOX):c.-432-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 248,344 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006883.2 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHOX | NM_006883.2 | c.-432-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHOX | ENST00000334060.8 | c.-432-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | |||||
SHOX | ENST00000381578.6 | c.-432-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74340
GnomAD4 exome AF: 0.000104 AC: 10AN: 96154Hom.: 0 Cov.: 0 AF XY: 0.0000799 AC XY: 4AN XY: 50048
GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74340
ClinVar
Submissions by phenotype
Leri-Weill dyschondrosteosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 26, 2022 | Variant summary: SHOX c.-432-3C>A alters a non-conserved nucleotide located close to a canonical splice site at the intron 1 and exon 2 boundary, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant weakens the 3' acceptor site. At least one publication reported experimental evidence, demonstrating in a minigene assay that the variant abolished normal splicing (Danzig_2012); however, authors of the study also noted that the SHOX gene might have an alternative promoter within exon 2, which should be unaffected by this splice acceptor site mutation in intron 1, which could generate a transcript and a fully functional Shox protein. The SHOX gene is located in the pseudoautosomal region of the X and Y chromosomes, and the variant allele was found at a frequency of 0.00017 in 150962 control chromosomes (gnomAD v3.1, genomes dataset), predominantly within the Ashkenazi Jewish subpopulation at a frequency of 0.0063 (i.e. 22/3468 alleles, all heterozygotes). The variant, c.-432-3C>A, has been reported in the literature in multiple heterozygous carriers who were affected with Short Stature (Danzig_2012, Shapiro_2015), and in one homozygous individual, who was affected with a more extreme short stature than his heterozygous children, but lacked features of Langer mesomelic dysplasia, suggesting that even if the variant affects splicing in vivo, some functional Shox protein was still produced (Danzig_2012). Since the expressivity of SHOX deficiency is highly variable (PMID: 21325865), these data indicate that the variant in heterozygous- or in homozygous state maybe associated with Short Stature, but it is unclear if it could contribute to more severe phenotypes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for Short Stature phenotype. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at