chr2-147938138-AATCTT-A

Variant names:

• chr2-147938138-AATCTT-A
• NM_181741.4:c.1122+3_1122+7delAAGAT

Variant summary

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

The NM_181741.4(ORC4):​c.1122+3_1122+7delAAGAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,440,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ORC4 NM_181741.4 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59
• 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.1122+3_1122+7delAAGAT		splice_region intron	N/A	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.1122+3_1122+7delAAGAT		splice_region intron	N/A	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.1122+3_1122+7delAAGAT		splice_region intron	N/A	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.1122+3_1122+7delAAGAT		splice_region intron	N/A	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.1122+3_1122+7delAAGAT		splice_region intron	N/A	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.1122+3_1122+7delAAGAT		splice_region intron	N/A	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1440508 Hom.: 0 AF XY: 0.00000557 AC XY: 4 AN XY: 718088

African (AFR) AF: 0.00 AC: 0 AN: 33006

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39340

South Asian (SAS) AF: 0.00 AC: 0 AN: 85746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1093208

Other (OTH) AF: 0.0000335 AC: 2 AN: 59630

GnomAD4 genome Cov.: 32

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
PhyloP100		2.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-148695707;