2-147943530-GAAAAAA-GAAAAAAAA

Variant names:

• chr2-147943530-G-GAA
• rs66919703
• NM_181741.4:c.763-10_763-9dupTT

Variant summary

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

The NM_181741.4(ORC4):​c.763-10_763-9dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ORC4 NM_181741.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	NM_181741.4	MANE Select	c.763-10_763-9dupTT		intron	N/A	NP_859525.1
	ORC4	NM_001190879.3		c.763-10_763-9dupTT		intron	N/A	NP_001177808.1
	ORC4	NM_001374270.1		c.763-10_763-9dupTT		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.763-9_763-8insTT		intron	N/A	ENSP00000376597.5
	ORC4	ENST00000264169.6	TSL:5	c.763-9_763-8insTT		intron	N/A	ENSP00000264169.2
	ORC4	ENST00000535373.5	TSL:5	c.763-9_763-8insTT		intron	N/A	ENSP00000441953.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 131288 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 128 AN: 1037182 Hom.: 0 Cov.: 0 AF XY: 0.000115 AC XY: 61 AN XY: 531436

⚠️ 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: 24020

American (AMR) AF: 0.0000785 AC: 3 AN: 38198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22346

East Asian (EAS) AF: 0.00 AC: 0 AN: 36342

South Asian (SAS) AF: 0.0000830 AC: 6 AN: 72308

European-Finnish (FIN) AF: 0.0000228 AC: 1 AN: 43896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4378

European-Non Finnish (NFE) AF: 0.000153 AC: 115 AN: 749896

Other (OTH) AF: 0.0000655 AC: 3 AN: 45798

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 131288 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 63336

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: 0.00 AC: 0 AN: 7314

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59322

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11

Splicing

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

Other links and lift over

dbSNP: rs66919703; hg19: chr2-148701099;