rs797044461
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_181741.4(ORC4):c.870_873dupAACA(p.Ala292AsnfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,611,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_181741.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251060Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135668
GnomAD4 exome AF: 0.0000206 AC: 30AN: 1459780Hom.: 0 Cov.: 29 AF XY: 0.0000151 AC XY: 11AN XY: 726308
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74276
ClinVar
Submissions by phenotype
Meier-Gorlin syndrome 2 Pathogenic:1
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not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Meier-Gorlin syndrome (PMID: 21358631, 21358632). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.874_875insAACA. ClinVar contains an entry for this variant (Variation ID: 30296). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala292Asnfs*20) in the ORC4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ORC4 are known to be pathogenic (PMID: 21358631, 22333897, 21358632). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at