rs61750441

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_181741.4(ORC4):​c.353T>C​(p.Leu118Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,612,158 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0026 ( 9 hom. )

Consequence

ORC4
NM_181741.4 missense

Scores

9
7
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 8.83

Publications

8 publications found
Variant links:
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 2
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
  • Meier-Gorlin syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.14341849).
BP6
Variant 2-147958332-A-G is Benign according to our data. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806. Variant chr2-147958332-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 211806.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00143 (218/152196) while in subpopulation NFE AF = 0.00233 (158/67940). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ORC4NM_181741.4 linkc.353T>C p.Leu118Ser missense_variant Exon 6 of 14 ENST00000392857.10 NP_859525.1 O43929-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ORC4ENST00000392857.10 linkc.353T>C p.Leu118Ser missense_variant Exon 6 of 14 1 NM_181741.4 ENSP00000376597.5 O43929-1

Frequencies

GnomAD3 genomes
AF:
0.00143
AC:
218
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000651
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00151
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00233
Gnomad OTH
AF:
0.00143
GnomAD2 exomes
AF:
0.00161
AC:
403
AN:
250922
AF XY:
0.00168
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00101
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000463
Gnomad NFE exome
AF:
0.00259
Gnomad OTH exome
AF:
0.000981
GnomAD4 exome
AF:
0.00255
AC:
3727
AN:
1459962
Hom.:
9
Cov.:
29
AF XY:
0.00251
AC XY:
1820
AN XY:
726348
show subpopulations
African (AFR)
AF:
0.000359
AC:
12
AN:
33424
American (AMR)
AF:
0.00112
AC:
50
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26100
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39536
South Asian (SAS)
AF:
0.00182
AC:
157
AN:
86134
European-Finnish (FIN)
AF:
0.000544
AC:
29
AN:
53348
Middle Eastern (MID)
AF:
0.00122
AC:
7
AN:
5752
European-Non Finnish (NFE)
AF:
0.00299
AC:
3319
AN:
1110672
Other (OTH)
AF:
0.00254
AC:
153
AN:
60302
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.464
Heterozygous variant carriers
0
154
307
461
614
768
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
128
256
384
512
640
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00143
AC:
218
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.00124
AC XY:
92
AN XY:
74404
show subpopulations
African (AFR)
AF:
0.000649
AC:
27
AN:
41580
American (AMR)
AF:
0.00151
AC:
23
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000829
AC:
4
AN:
4828
European-Finnish (FIN)
AF:
0.000283
AC:
3
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00233
AC:
158
AN:
67940
Other (OTH)
AF:
0.00142
AC:
3
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
12
23
35
46
58
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00212
Hom.:
0
Bravo
AF:
0.00166
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00311
AC:
12
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00314
AC:
27
ExAC
AF:
0.00164
AC:
199
Asia WGS
AF:
0.000578
AC:
2
AN:
3476
EpiCase
AF:
0.00317
EpiControl
AF:
0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Sep 17, 2015
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Dec 05, 2014
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ORC4-related disorder Benign:1
Jul 29, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.076
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
.;T;.;T;T;T;.;T
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;.;.;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.14
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.27
D
MutationAssessor
Pathogenic
3.9
.;H;.;H;H;.;.;.
PhyloP100
8.8
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-4.9
D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;.;D;.
Polyphen
1.0
.;D;.;D;D;.;.;.
Vest4
0.99
MVP
0.92
MPC
0.58
ClinPred
0.20
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.87
Mutation Taster
=82/18
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs61750441; hg19: chr2-148715901; COSMIC: COSV99068414; COSMIC: COSV99068414; API