chr2-147943530-GAAAAAA-G

Variant names:

• chr2-147943530-GAAAAAA-G
• rs66919703
• NM_181741.4:c.763-14_763-9delTTTTTT

Variant summary

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

The NM_181741.4(ORC4):​c.763-14_763-9delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000964 in 1,037,666 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: not found (cov: 0)
  • Exomes 𝑓: 9.6e-7 (0 hom.)
• Consequence: ORC4 NM_181741.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.401
• 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 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	NM_181741.4	MANE Select	c.763-14_763-9delTTTTTT		intron	N/A	NP_859525.1
	ORC4	NM_001190879.3		c.763-14_763-9delTTTTTT		intron	N/A	NP_001177808.1
	ORC4	NM_001374270.1		c.763-14_763-9delTTTTTT		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.763-14_763-9delTTTTTT		intron	N/A	ENSP00000376597.5
	ORC4	ENST00000264169.6	TSL:5	c.763-14_763-9delTTTTTT		intron	N/A	ENSP00000264169.2
	ORC4	ENST00000535373.5	TSL:5	c.763-14_763-9delTTTTTT		intron	N/A	ENSP00000441953.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 9.64e-7 AC: 1 AN: 1037666 Hom.: 0 AF XY: 0.00000188 AC XY: 1 AN XY: 531678

⚠️ 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: 0.00 AC: 0 AN: 38204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22350

East Asian (EAS) AF: 0.00 AC: 0 AN: 36346

South Asian (SAS) AF: 0.00 AC: 0 AN: 72324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4382

European-Non Finnish (NFE) AF: 0.00000133 AC: 1 AN: 750322

Other (OTH) AF: 0.00 AC: 0 AN: 45812

⚠️ 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.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40

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;