2-147943530-GAAAAAA-GAA

Variant names:

• chr2-147943530-GAAAA-G
• rs66919703
• NM_181741.4:c.763-12_763-9delTTTT

Variant summary

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

The NM_181741.4(ORC4):​c.763-12_763-9delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,167,740 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 0.000015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ORC4 NM_181741.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.120
• 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: 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.763-12_763-9delTTTT		intron	N/A	NP_859525.1
	ORC4	NM_001190879.3		c.763-12_763-9delTTTT		intron	N/A	NP_001177808.1
	ORC4	NM_001374270.1		c.763-12_763-9delTTTT		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.763-12_763-9delTTTT		intron	N/A	ENSP00000376597.5
	ORC4	ENST00000264169.6	TSL:5	c.763-12_763-9delTTTT		intron	N/A	ENSP00000264169.2
	ORC4	ENST00000535373.5	TSL:5	c.763-12_763-9delTTTT		intron	N/A	ENSP00000441953.1

Frequencies

GnomAD3 genomes AF: 0.0000152 AC: 2 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: 0.0000337

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000819 AC: 138 AN: 168506 AF XY: 0.000840

Gnomad AFR exome AF: 0.000367

Gnomad AMR exome AF: 0.000707

Gnomad ASJ exome AF: 0.000954

Gnomad EAS exome AF: 0.000712

Gnomad FIN exome AF: 0.000943

Gnomad NFE exome AF: 0.000994

Gnomad OTH exome AF: 0.000941

GnomAD4 exome AF: 0.000264 AC: 274 AN: 1036452 Hom.: 0 AF XY: 0.000239 AC XY: 127 AN XY: 531060

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

African (AFR) AF: 0.000292 AC: 7 AN: 23970

American (AMR) AF: 0.000498 AC: 19 AN: 38122

Ashkenazi Jewish (ASJ) AF: 0.000179 AC: 4 AN: 22328

East Asian (EAS) AF: 0.000138 AC: 5 AN: 36266

South Asian (SAS) AF: 0.000180 AC: 13 AN: 72276

European-Finnish (FIN) AF: 0.000319 AC: 14 AN: 43838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4380

European-Non Finnish (NFE) AF: 0.000267 AC: 200 AN: 749512

Other (OTH) AF: 0.000262 AC: 12 AN: 45760

⚠️ 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: 0.0000152 AC: 2 AN: 131288 Hom.: 0 Cov.: 0 AF XY: 0.0000158 AC XY: 1 AN XY: 63336

⚠️ 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: 0.00 AC: 0 AN: 7314

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

European-Non Finnish (NFE) AF: 0.0000337 AC: 2 AN: 59322

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: 0.00 Hom.: 288

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
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;