rs3087476

Variant names:

• chr1-52389289-G-A
• rs3087476
• NM_004153.4:c.1115C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004153.4(ORC1):​c.1115C>T​(p.Ala372Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,613,960 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A372P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 32)
  • Exomes 𝑓: 0.017 (229 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.46
• Publications: 14 publications found

Genes affected

ORC1 (HGNC:8487): (origin recognition complex subunit 1) The origin recognition complex (ORC) is a highly conserved six subunits 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. The protein encoded by this gene is the largest subunit of the ORC complex. While other ORC subunits are stable throughout the cell cycle, the levels of this protein vary during the cell cycle, which has been shown to be controlled by ubiquitin-mediated proteolysis after initiation of DNA replication. This protein is found to be selectively phosphorylated during mitosis. It is also reported to interact with MYST histone acetyltransferase 2 (MyST2/HBO1), a protein involved in control of transcription silencing. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ORC1 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 1

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033430457).
• BP6: Variant 1-52389289-G-A is Benign according to our data. Variant chr1-52389289-G-A is described in ClinVar as Benign. ClinVar VariationId is 129854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0136 (2067/152294) while in subpopulation AMR AF = 0.0199 (305/15290). AF 95% confidence interval is 0.0187. There are 21 homozygotes in GnomAd4. There are 973 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004153.4. 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
	ORC1	NM_004153.4	MANE Select	c.1115C>T	p.Ala372Val	missense	Exon 7 of 17	NP_004144.2
	ORC1	NM_001190818.2		c.1115C>T	p.Ala372Val	missense	Exon 7 of 17	NP_001177747.1
	ORC1	NM_001190819.2		c.1115C>T	p.Ala372Val	missense	Exon 7 of 17	NP_001177748.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	ENST00000371568.8	TSL:1 MANE Select	c.1115C>T	p.Ala372Val	missense	Exon 7 of 17	ENSP00000360623.3
	ORC1	ENST00000371566.1	TSL:1	c.1115C>T	p.Ala372Val	missense	Exon 7 of 17	ENSP00000360621.1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2064 AN: 152178 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.0151 AC: 3797 AN: 251474 AF XY: 0.0150

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00966

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0168 AC: 24506 AN: 1461666 Hom.: 229 Cov.: 31 AF XY: 0.0166 AC XY: 12069 AN XY: 727154

African (AFR) AF: 0.00266 AC: 89 AN: 33478

American (AMR) AF: 0.0233 AC: 1040 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 644 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00436 AC: 376 AN: 86258

European-Finnish (FIN) AF: 0.0103 AC: 551 AN: 53406

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5766

European-Non Finnish (NFE) AF: 0.0187 AC: 20744 AN: 1111818

Other (OTH) AF: 0.0158 AC: 955 AN: 60384

GnomAD4 genome AF: 0.0136 AC: 2067 AN: 152294 Hom.: 21 Cov.: 32 AF XY: 0.0131 AC XY: 973 AN XY: 74470

African (AFR) AF: 0.00390 AC: 162 AN: 41562

American (AMR) AF: 0.0199 AC: 305 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

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

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4826

European-Finnish (FIN) AF: 0.00773 AC: 82 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0196 AC: 1335 AN: 68026

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.0176 Hom.: 101

Bravo AF: 0.0149

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0149 AC: 1810

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0222

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Meier-Gorlin syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.16	T
Polyphen		0.21	B
Vest4		0.062
MPC		0.16
ClinPred		0.0069	T
GERP RS		3.2
Varity_R		0.021
gMVP		0.17
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3087476; hg19: chr1-52854961; COSMIC: COSV65365373;