chr16-46689707-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PVS1_ModeratePM2PP5BS1_Supporting
The NM_014321.4(ORC6):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,600,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014321.4 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ORC6 | NM_014321.4 | c.2T>C | p.Met1? | start_lost | Exon 1 of 7 | ENST00000219097.7 | NP_055136.1 | |
ORC6 | XM_011522978.4 | c.2T>C | p.Met1? | start_lost | Exon 1 of 6 | XP_011521280.1 | ||
ORC6 | NR_037620.2 | n.49T>C | non_coding_transcript_exon_variant | Exon 1 of 7 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000355 AC: 54AN: 152038Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000283 AC: 63AN: 222746Hom.: 0 AF XY: 0.000223 AC XY: 27AN XY: 121052
GnomAD4 exome AF: 0.000590 AC: 855AN: 1448794Hom.: 0 Cov.: 33 AF XY: 0.000573 AC XY: 412AN XY: 719430
GnomAD4 genome AF: 0.000348 AC: 53AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74412
ClinVar
Submissions by phenotype
not provided Pathogenic:5Uncertain:1
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Initiation codon variant in a gene for which loss of function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 29431110, 34426522, 31589614, 36012502, 22333897) -
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This sequence change affects the initiator methionine of the ORC6 mRNA. The next in-frame methionine is located at codon 20. This variant is present in population databases (rs146795505, gnomAD 0.06%). Disruption of the initiator codon has been observed in individual(s) with Meier–Gorlin syndrome (PMID: 22333897, 36012502). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 253272). For these reasons, this variant has been classified as Pathogenic. -
Meier-Gorlin syndrome 3 Pathogenic:5
The ORC6 c.2T>C; p.Met1? variant (rs146795505, ClinVar Variation ID: 253272) is reported in the literature in at least four probands affected with Meier-Gorlin syndrome, all of whom carried the c.449+5G>A variant in trans (de Munnik 2012, Nazarenko 2022). This variant is found in the general population with an overall allele frequency of 0.03% (75/254,098 alleles) in the Genome Aggregation Database (v2.1.1). This variant abolishes the canonical translation initiation site, which is likely to disrupt gene function; however, it is not known if downstream in-frame initiation sites could be used. Based on available information, this variant is considered to be likely pathogenic. References: de Munnik SA et al. Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. Eur J Hum Genet. 2012 Jun;20(6):598-606. PMID: 22333897. Nazarenko MS et al. Meier-Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test. Int J Mol Sci. 2022 Aug 17;23(16):9234. PMID: 36012502. -
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Variant summary: ORC6 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 222746 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ORC6 causing Meier-Gorlin Syndrome 3, allowing no conclusion about variant significance. c.2T>C has been reported in the literature in compound heterozygous individuals affected with Meier-Gorlin Syndrome 3 (de Munnik_2012, Nazarenko_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36012502, 22333897). ClinVar contains an entry for this variant (Variation ID: 253272). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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The ORC6 c.2T>C (p.Met1?) variant is a stop-lost variant that is predicted to result in an elongation of the protein. This variant has been reported in one study and is found in a compound heterozygous state in four individuals from three families with Meier-Gorlin syndrome (De Munnik et al. 2012). The p.Met1? variant is reported at a frequency of 0.000601 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Met1? variant is classified likely pathogenic for Meier-Gorlin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
ORC6-related disorder Pathogenic:1
The ORC6 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). This variant along with another ORC6 splicing variant has been reported in four patients from three families with autosomal recessive Meier-Gorlin syndrome (de Munnik. 2012. PubMed ID: 22333897, see table 2). This variant in the heterozygous condition was reported in another patient with autosomal recessive Meier-Gorlin syndrome, a second plausible causative ORC6 variant was not described (Reuter et al. 2018. PubMed ID: 29431110, see appendix table S1).This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at