rs797044461
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
ORC4
NM_181741.4 frameshift
NM_181741.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.472
Publications
2 publications found
Genes affected
ORC4 (HGNC:8490): (origin recognition complex subunit 4) The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]
ORC4 Gene-Disease associations (from GenCC):
- Meier-Gorlin syndrome 2Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- Meier-Gorlin syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 2-147939224-C-CTGTT is Pathogenic according to our data. Variant chr2-147939224-C-CTGTT is described in ClinVar as Pathogenic. ClinVar VariationId is 30296.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_181741.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ORC4 | MANE Select | c.870_873dupAACA | p.Ala292AsnfsTer20 | frameshift | Exon 11 of 14 | NP_859525.1 | O43929-1 | ||
| ORC4 | c.870_873dupAACA | p.Ala292AsnfsTer20 | frameshift | Exon 12 of 15 | NP_001177808.1 | O43929-1 | |||
| ORC4 | c.870_873dupAACA | p.Ala292AsnfsTer20 | frameshift | Exon 13 of 16 | NP_001361199.1 | O43929-1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ORC4 | TSL:1 MANE Select | c.870_873dupAACA | p.Ala292AsnfsTer20 | frameshift | Exon 11 of 14 | ENSP00000376597.5 | O43929-1 | ||
| ORC4 | c.870_873dupAACA | p.Ala292AsnfsTer20 | frameshift | Exon 11 of 15 | ENSP00000547993.1 | ||||
| ORC4 | TSL:5 | c.870_873dupAACA | p.Ala292AsnfsTer20 | frameshift | Exon 11 of 14 | ENSP00000264169.2 | O43929-1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152092
Hom.:
Cov.:
32
Gnomad AFR
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Gnomad AMI
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Gnomad FIN
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Gnomad NFE
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Gnomad OTH
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GnomAD2 exomes AF: 0.0000119 AC: 3AN: 251060 AF XY: 0.00000737 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
251060
AF XY:
Gnomad AFR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.0000206 AC: 30AN: 1459780Hom.: 0 Cov.: 29 AF XY: 0.0000151 AC XY: 11AN XY: 726308 show subpopulations
GnomAD4 exome
AF:
AC:
30
AN:
1459780
Hom.:
Cov.:
29
AF XY:
AC XY:
11
AN XY:
726308
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33412
American (AMR)
AF:
AC:
0
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26088
East Asian (EAS)
AF:
AC:
0
AN:
39644
South Asian (SAS)
AF:
AC:
0
AN:
86218
European-Finnish (FIN)
AF:
AC:
0
AN:
53378
Middle Eastern (MID)
AF:
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
30
AN:
1110286
Other (OTH)
AF:
AC:
0
AN:
60286
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
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Allele balance
Age Distribution
Exome Het
Variant carriers
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>80
Age
GnomAD4 genome 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74276 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152092
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74276
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41412
American (AMR)
AF:
AC:
0
AN:
15254
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3468
East Asian (EAS)
AF:
AC:
0
AN:
5186
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68022
Other (OTH)
AF:
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Meier-Gorlin syndrome 2 (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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