chr2-147943530-GA-G

Variant names:

• chr2-147943530-GA-G
• rs66919703
• NM_181741.4:c.763-9delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_181741.4(ORC4):​c.763-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (14965 hom., cov: 0)
  • Exomes 𝑓: 0.43 (5650 hom.)
  • Failed GnomAD Quality Control
• Consequence: ORC4 NM_181741.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-147943530-GA-G is Benign according to our data. Variant chr2-147943530-GA-G is described in ClinVar as Benign. ClinVar VariationId is 403280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.499 AC: 65366 AN: 131084 Hom.: 14972 Cov.: 0

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.594

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.513

GnomAD2 exomes AF: 0.472 AC: 79580 AN: 168506 AF XY: 0.472

Gnomad AFR exome AF: 0.484

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.482

Gnomad FIN exome AF: 0.463

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.471

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.430 AC: 426378 AN: 990950 Hom.: 5650 Cov.: 0 AF XY: 0.433 AC XY: 218765 AN XY: 505422

African (AFR) AF: 0.469 AC: 10994 AN: 23452

American (AMR) AF: 0.454 AC: 16679 AN: 36698

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 9495 AN: 20878

East Asian (EAS) AF: 0.470 AC: 16356 AN: 34782

South Asian (SAS) AF: 0.445 AC: 29061 AN: 65334

European-Finnish (FIN) AF: 0.443 AC: 18258 AN: 41198

Middle Eastern (MID) AF: 0.470 AC: 2001 AN: 4260

European-Non Finnish (NFE) AF: 0.422 AC: 304474 AN: 720788

Other (OTH) AF: 0.438 AC: 19060 AN: 43560

GnomAD4 genome AF: 0.499 AC: 65367 AN: 131102 Hom.: 14965 Cov.: 0 AF XY: 0.498 AC XY: 31508 AN XY: 63274

African (AFR) AF: 0.613 AC: 22628 AN: 36892

American (AMR) AF: 0.505 AC: 6675 AN: 13222

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1350 AN: 3082

East Asian (EAS) AF: 0.556 AC: 2534 AN: 4554

South Asian (SAS) AF: 0.386 AC: 1534 AN: 3976

European-Finnish (FIN) AF: 0.435 AC: 3173 AN: 7296

Middle Eastern (MID) AF: 0.582 AC: 142 AN: 244

European-Non Finnish (NFE) AF: 0.440 AC: 26058 AN: 59226

Other (OTH) AF: 0.511 AC: 938 AN: 1834

Alfa AF: 0.295 Hom.: 288

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Meier-Gorlin syndrome 2 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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;