2-147939202-G-A

Variant names:

• chr2-147939202-G-A
• rs776141895
• NM_181741.4:c.896C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181741.4(ORC4):​c.896C>T​(p.Ala299Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,612,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16599223).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	NM_181741.4	MANE Select	c.896C>T	p.Ala299Val	missense	Exon 11 of 14	NP_859525.1
	ORC4	NM_001190879.3		c.896C>T	p.Ala299Val	missense	Exon 12 of 15	NP_001177808.1
	ORC4	NM_001374270.1		c.896C>T	p.Ala299Val	missense	Exon 13 of 16	NP_001361199.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	ENST00000392857.10	TSL:1 MANE Select	c.896C>T	p.Ala299Val	missense	Exon 11 of 14	ENSP00000376597.5
	ORC4	ENST00000264169.6	TSL:5	c.896C>T	p.Ala299Val	missense	Exon 11 of 14	ENSP00000264169.2
	ORC4	ENST00000535373.5	TSL:5	c.896C>T	p.Ala299Val	missense	Exon 12 of 15	ENSP00000441953.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251114 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460874 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726768

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111228

Other (OTH) AF: 0.0000166 AC: 1 AN: 60346

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74258

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15254

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.60
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.27
Sift	Benign	0.74	T
Sift4G	Benign	0.95	T
Polyphen		0.038	B
Vest4		0.26
MutPred		0.33		Gain of catalytic residue at A299 (P = 0.1924)
MVP		0.87
MPC		0.094
ClinPred		0.14	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.30
Mutation Taster		=56/44	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: rs776141895; hg19: chr2-148696771;