chr2-147938157-C-T

Variant names:

• chr2-147938157-C-T
• rs1688159655
• NM_181741.4:c.1111G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181741.4(ORC4):​c.1111G>A​(p.Val371Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1111G>A	p.Val371Ile	missense	Exon 13 of 14	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.1111G>A	p.Val371Ile	missense	Exon 14 of 15	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.1111G>A	p.Val371Ile	missense	Exon 15 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.1111G>A	p.Val371Ile	missense	Exon 13 of 14	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.1111G>A	p.Val371Ile	missense	Exon 13 of 15	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.1111G>A	p.Val371Ile	missense	Exon 13 of 14	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.38
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Polyphen		0.91	P
Vest4		0.49
MutPred		0.77		Gain of ubiquitination at K374 (P = 0.0754)
MVP		0.83
MPC		0.36
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.44
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs1688159655; hg19: chr2-148695726;