1-52372955-C-T

Variant names:

• chr1-52372955-C-T
• rs886046395
• NM_004153.4:c.*226G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004153.4(ORC1):​c.*226G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 391,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: ORC1 NM_004153.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.188
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	NM_004153.4	MANE Select	c.*226G>A		3_prime_UTR	Exon 17 of 17	NP_004144.2
	ORC1	NM_001190818.2		c.*226G>A		3_prime_UTR	Exon 17 of 17	NP_001177747.1	Q13415
	ORC1	NM_001190819.2		c.*226G>A		3_prime_UTR	Exon 17 of 17	NP_001177748.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	ENST00000371568.8	TSL:1 MANE Select	c.*226G>A		3_prime_UTR	Exon 17 of 17	ENSP00000360623.3	Q13415
	ORC1	ENST00000371566.1	TSL:1	c.*226G>A		3_prime_UTR	Exon 17 of 17	ENSP00000360621.1	Q13415
	ORC1	ENST00000959732.1		c.*226G>A		3_prime_UTR	Exon 16 of 16	ENSP00000629791.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000255 AC: 1 AN: 391710 Hom.: 0 Cov.: 3 AF XY: 0.00000477 AC XY: 1 AN XY: 209430

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11348

American (AMR) AF: 0.00 AC: 0 AN: 18094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11942

East Asian (EAS) AF: 0.00 AC: 0 AN: 24494

South Asian (SAS) AF: 0.00 AC: 0 AN: 47242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1640

European-Non Finnish (NFE) AF: 0.00000431 AC: 1 AN: 231866

Other (OTH) AF: 0.00 AC: 0 AN: 22114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.87
DANN	Benign	0.36
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886046395; hg19: chr1-52838627;