6-136825272-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000288.4(PEX7):c.188+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000274 in 1,457,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000288.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX7 | NM_000288.4 | c.188+1G>C | splice_donor_variant, intron_variant | Intron 2 of 9 | ENST00000318471.5 | NP_000279.1 | ||
PEX7 | NM_001410945.1 | c.74+1G>C | splice_donor_variant, intron_variant | Intron 2 of 9 | NP_001397874.1 | |||
PEX7 | XM_006715502.3 | c.188+1G>C | splice_donor_variant, intron_variant | Intron 2 of 6 | XP_006715565.1 | |||
PEX7 | XM_047418874.1 | c.188+1G>C | splice_donor_variant, intron_variant | Intron 2 of 5 | XP_047274830.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251450Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457484Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 725396
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rhizomelic chondrodysplasia punctata type 1 Pathogenic:3
NM_000288.3(PEX7):c.188+1G>C is a canonical splice variant classified as likely pathogenic in the context of rhizomelic chondrodysplasia punctata type 1. c.188+1G>C has been observed in a case with relevant disease (PMID: 12325024). Functional assessments of this variant are not available in the literature. c.188+1G>C has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, NM_000288.3(PEX7):c.188+1G>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
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Variant summary: PEX7 c.188+1G>C (also known as IVS2+1G>C) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. At-least one in-silico prediction tool, Transcript-inferred Pathogenicity score (TraP), predicts a possible pathogenic outcome for this variant. The variant allele was found at a frequency of 1.2e-05 in 251450 control chromosomes (gnomAD). c.188+1G>C has been reported in the literature in individuals affected with Rhizomelic Chondrodysplasia Punctata Type 1 (e.g. Braverman_2002). These data indicate that the variant is likely to be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Peroxisome biogenesis disorder 9B Pathogenic:2
This sequence change affects a donor splice site in intron 2 of the PEX7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX7 are known to be pathogenic (PMID: 12325024, 12522768, 20301447). This variant is present in population databases (rs267608254, gnomAD 0.009%). Disruption of this splice site has been observed in individuals with rhizomelic chondrodysplasia punctata (PMID: 12325024). This variant is also known as IVS2+1G>C. ClinVar contains an entry for this variant (Variation ID: 188975). Studies have shown that disruption of this splice site alters PEX7 gene expression (PMID: 12325024). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31589614, 31964843, 12325024) -
Phytanic acid storage disease;C1859133:Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at