rs267608255
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000288.4(PEX7):c.340-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,551,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000288.4 splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX7 | NM_000288.4 | c.340-10A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000318471.5 | |||
PEX7 | NM_001410945.1 | c.226-10A>G | splice_polypyrimidine_tract_variant, intron_variant | ||||
PEX7 | XM_006715502.3 | c.339+19136A>G | intron_variant | ||||
PEX7 | XM_047418874.1 | c.340-10A>G | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX7 | ENST00000318471.5 | c.340-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000288.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000127 AC: 32AN: 251386Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135870
GnomAD4 exome AF: 0.0000672 AC: 94AN: 1399318Hom.: 0 Cov.: 27 AF XY: 0.0000686 AC XY: 48AN XY: 699958
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74364
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder 9B Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change falls in intron 3 of the PEX7 gene. It does not directly change the encoded amino acid sequence of the PEX7 protein. This variant is present in population databases (rs267608255, gnomAD 0.2%). This variant has been observed in individual(s) with rhizomelic chondrodysplasia punctata (PMID: 12325024). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS3-10A>G. ClinVar contains an entry for this variant (Variation ID: 7787). 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. - |
Rhizomelic chondrodysplasia punctata type 1 Pathogenic:2Uncertain:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2024 | Variant summary: PEX7 c.340-10A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splicing acceptor site, one predicts the variant weakens this site, and three predict the variant creates a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing presumably by nonsense mediated decay, although low levels of normal PEX7 transcript was also detected (Braverman_2002). The variant allele was found at a frequency of 0.00013 in 251386 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PEX7 causing Rhizomelic Chondrodysplasia Punctata Type 1 (0.00013 vs 0.0019), allowing no conclusion about variant significance. c.340-10A>G has been reported in the literature as a compound heterozygous genotype with other pathogenic variants in at-least two individuals, one affected with Rhizomelic Chondrodysplasia Punctata Type 1 and the other with milder features of adult Refsum disease (Braverman_2002). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12325024, 14974078, 25851898). ClinVar contains an entry for this variant (Variation ID: 7787). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The PEX7 c.340-10A>G variant is an intron variant that has been reported in one study by Braverman et al. (2002), in which it was found in a compound heterozygous state in two unrelated individuals with rhizomelic chondrodysplasia punctata. One of these individuals had a splice site variant as the second allele, and one had a stop-gained variant. The c.340-10A>G variant was absent from at least 100 control chromosomes and is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR studies demonstrated that the c.340-10A>G variant produced lower levels of mRNA compared to wildtype, which is consistent with the milder disease phenotype in the patients. Based on the available evidence, the c.340-10A>G variant is considered to be a variant of unknown significance but suspicious for pathogenicity for rhizomelic chondrodysplasia punctata. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 19, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 29, 2017 | - - |
Phytanic acid storage disease Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.340-10A>G variant has been reported in one study by Braverman et al. (2002) in which it was found in a compound heterozygous state in two unrelated individuals with rhizomelic chondrodysplasia punctata, one with a splice site variant and one with a stop-gained variant as the second allele. The c.340-10A>G variant was absent from at least 100 control chromosomes but is reported at a frequency of 0.00019 in the European (Non-Finnish) population of the Exome Aggregation Consortium. RT-PCR studies demonstrated that the c.340-10A>G variant produced lower levels of mRNA compared to wildtype, which is consistent with the milder disease phenotype in the patients. Based on the available evidence, the c.340-10A>G variant is classified as a variant of unknown significance but suspicious for pathogenicity for rhizomelic chondrodysplasia punctata. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at