2-147943526-A-C

Variant names:

• chr2-147943526-A-C
• rs769409347
• NM_181741.4:c.763-4T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_181741.4(ORC4):​c.763-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000418 in 1,505,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: ORC4 NM_181741.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001233
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.09
• 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: 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.763-4T>G		splice_region intron	N/A	NP_859525.1
	ORC4	NM_001190879.3		c.763-4T>G		splice_region intron	N/A	NP_001177808.1
	ORC4	NM_001374270.1		c.763-4T>G		splice_region intron	N/A	NP_001361199.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	ENST00000392857.10	TSL:1 MANE Select	c.763-4T>G		splice_region intron	N/A	ENSP00000376597.5
	ORC4	ENST00000264169.6	TSL:5	c.763-4T>G		splice_region intron	N/A	ENSP00000264169.2
	ORC4	ENST00000535373.5	TSL:5	c.763-4T>G		splice_region intron	N/A	ENSP00000441953.1

Frequencies

GnomAD3 genomes AF: 0.0000414 AC: 5 AN: 120788 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000168

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: 0.0000343

Gnomad OTH AF: 0.000631

GnomAD2 exomes AF: 0.000120 AC: 23 AN: 192252 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000806

Gnomad OTH exome AF: 0.000402

GnomAD4 exome AF: 0.0000419 AC: 58 AN: 1384700 Hom.: 0 Cov.: 23 AF XY: 0.0000519 AC XY: 36 AN XY: 693076

African (AFR) AF: 0.00 AC: 0 AN: 31928

American (AMR) AF: 0.000295 AC: 13 AN: 44048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25504

East Asian (EAS) AF: 0.00 AC: 0 AN: 39212

South Asian (SAS) AF: 0.0000949 AC: 8 AN: 84260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51324

Middle Eastern (MID) AF: 0.000536 AC: 3 AN: 5602

European-Non Finnish (NFE) AF: 0.0000230 AC: 24 AN: 1044972

Other (OTH) AF: 0.000173 AC: 10 AN: 57850

GnomAD4 genome AF: 0.0000414 AC: 5 AN: 120788 Hom.: 0 Cov.: 31 AF XY: 0.0000169 AC XY: 1 AN XY: 59070

African (AFR) AF: 0.00 AC: 0 AN: 27838

American (AMR) AF: 0.000168 AC: 2 AN: 11902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2966

East Asian (EAS) AF: 0.00 AC: 0 AN: 3876

South Asian (SAS) AF: 0.00 AC: 0 AN: 4152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000343 AC: 2 AN: 58326

Other (OTH) AF: 0.000631 AC: 1 AN: 1584

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	ORC4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.6
DANN	Benign	0.79
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0060
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: rs769409347; hg19: chr2-148701095;