2-147943530-GAAAAAA-GAAA

Variant names:

• chr2-147943530-GAAA-G
• rs66919703
• NM_181741.4:c.763-11_763-9delTTT

Variant summary

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

The NM_181741.4(ORC4):​c.763-11_763-9delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,159,244 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0035 (0 hom.)
• Consequence: ORC4 NM_181741.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 2 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 0 ACMG points.

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.763-11_763-9delTTT		intron	N/A	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.763-11_763-9delTTT		intron	N/A	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.763-11_763-9delTTT		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.763-11_763-9delTTT		intron	N/A	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.763-11_763-9delTTT		intron	N/A	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.763-11_763-9delTTT		intron	N/A	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes AF: 0.0000229 AC: 3 AN: 131276 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.000137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000337

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00846 AC: 1426 AN: 168506 AF XY: 0.00830

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.00719

Gnomad ASJ exome AF: 0.00286

Gnomad EAS exome AF: 0.0108

Gnomad FIN exome AF: 0.00912

Gnomad NFE exome AF: 0.00900

Gnomad OTH exome AF: 0.00470

GnomAD4 exome AF: 0.00347 AC: 3568 AN: 1027968 Hom.: 0 AF XY: 0.00340 AC XY: 1791 AN XY: 526900

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

African (AFR) AF: 0.00681 AC: 161 AN: 23644

American (AMR) AF: 0.00547 AC: 206 AN: 37638

Ashkenazi Jewish (ASJ) AF: 0.00239 AC: 53 AN: 22174

East Asian (EAS) AF: 0.00422 AC: 151 AN: 35794

South Asian (SAS) AF: 0.00270 AC: 194 AN: 71868

European-Finnish (FIN) AF: 0.00404 AC: 175 AN: 43368

Middle Eastern (MID) AF: 0.00277 AC: 12 AN: 4326

European-Non Finnish (NFE) AF: 0.00331 AC: 2463 AN: 743866

Other (OTH) AF: 0.00338 AC: 153 AN: 45290

⚠️ 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 AF: 0.0000229 AC: 3 AN: 131276 Hom.: 0 Cov.: 0 AF XY: 0.0000474 AC XY: 3 AN XY: 63324

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

African (AFR) AF: 0.00 AC: 0 AN: 36884

American (AMR) AF: 0.00 AC: 0 AN: 13234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3088

East Asian (EAS) AF: 0.00 AC: 0 AN: 4568

South Asian (SAS) AF: 0.00 AC: 0 AN: 4002

European-Finnish (FIN) AF: 0.000137 AC: 1 AN: 7314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000337 AC: 2 AN: 59310

Other (OTH) AF: 0.00 AC: 0 AN: 1832

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00340 Hom.: 288

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
Mutation Taster		=100/0	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: rs66919703; hg19: chr2-148701099;