rs140536267
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004153.4(ORC1):āc.2013G>Cā(p.Leu671=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000434 in 1,612,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_004153.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ORC1 | NM_004153.4 | c.2013G>C | p.Leu671= | splice_region_variant, synonymous_variant | 13/17 | ENST00000371568.8 | NP_004144.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ORC1 | ENST00000371568.8 | c.2013G>C | p.Leu671= | splice_region_variant, synonymous_variant | 13/17 | 1 | NM_004153.4 | ENSP00000360623 | P1 | |
ORC1 | ENST00000371566.1 | c.2013G>C | p.Leu671= | splice_region_variant, synonymous_variant | 13/17 | 1 | ENSP00000360621 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251414Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135880
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1460088Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33AN XY: 726344
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 02, 2021 | This sequence change affects codon 671 of the ORC1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ORC1 protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs140536267, ExAC 0.01%). This variant has been observed in individual(s) with clinical features of ORC1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 445650). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at