rs138317624

Variant names:

• chr2-147958805-T-C
• rs138317624
• NM_181741.4:c.287A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181741.4(ORC4):​c.287A>G​(p.Gln96Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000172 in 1,458,356 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.47
• Publications: 4 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 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010275394).
• BP6: Variant 2-147958805-T-C is Benign according to our data. Variant chr2-147958805-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159484.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000335 (51/152076) while in subpopulation EAS AF = 0.00964 (50/5188). AF 95% confidence interval is 0.00751. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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	NM_181741.4	MANE Select	c.287A>G	p.Gln96Arg	missense	Exon 5 of 14	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.287A>G	p.Gln96Arg	missense	Exon 6 of 15	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.287A>G	p.Gln96Arg	missense	Exon 7 of 16	NP_001361199.1	O43929-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	ENST00000392857.10	TSL:1 MANE Select	c.287A>G	p.Gln96Arg	missense	Exon 5 of 14	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.287A>G	p.Gln96Arg	missense	Exon 5 of 15	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.287A>G	p.Gln96Arg	missense	Exon 5 of 14	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151958 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000731 AC: 180 AN: 246182 AF XY: 0.000571

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00992

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 200 AN: 1306280 Hom.: 2 Cov.: 20 AF XY: 0.000155 AC XY: 102 AN XY: 657966

African (AFR) AF: 0.00 AC: 0 AN: 30480

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00512 AC: 198 AN: 38642

South Asian (SAS) AF: 0.00 AC: 0 AN: 82286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 971712

Other (OTH) AF: 0.0000181 AC: 1 AN: 55104

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 22 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00964 AC: 50 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67858

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000386 Hom.: 1

Bravo AF: 0.000272

ExAC AF: 0.000627 AC: 76

Asia WGS AF: 0.00116 AC: 4 AN: 3456

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Meier-Gorlin syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.067
Sift	Benign	0.037	D
Sift4G	Benign	0.27	T
Polyphen		0.69	P
Vest4		0.45
MVP		0.58
MPC		0.18
ClinPred		0.15	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.68
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs138317624; hg19: chr2-148716374;