2-147943530-GAAAAAA-GAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_181741.4(ORC4):​c.763-10_763-9delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 1,125,406 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 0)
  • Exomes 𝑓: 0.069 (2 hom.)
• Consequence: ORC4 NM_181741.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 2-147943530-GAA-G is Benign according to our data. Variant chr2-147943530-GAA-G is described in ClinVar as Benign. ClinVar VariationId is 403281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00209 (274/131268) while in subpopulation AFR AF = 0.00392 (145/36944). AF 95% confidence interval is 0.0034. There are 3 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.763-10_763-9delTT		intron	N/A	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.763-10_763-9delTT		intron	N/A	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.763-10_763-9delTT		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.763-10_763-9delTT		intron	N/A	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.763-10_763-9delTT		intron	N/A	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.763-10_763-9delTT		intron	N/A	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 275 AN: 131250 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00287

Gnomad ASJ AF: 0.000648

Gnomad EAS AF: 0.00153

Gnomad SAS AF: 0.000500

Gnomad FIN AF: 0.00192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000995

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.101 AC: 17017 AN: 168506 AF XY: 0.0998

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.0774

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.0912

Gnomad NFE exome AF: 0.0951

Gnomad OTH exome AF: 0.0868

GnomAD4 exome AF: 0.0694 AC: 68969 AN: 994138 Hom.: 2 AF XY: 0.0689 AC XY: 35039 AN XY: 508688

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

African (AFR) AF: 0.127 AC: 2858 AN: 22480

American (AMR) AF: 0.110 AC: 3955 AN: 35912

Ashkenazi Jewish (ASJ) AF: 0.0725 AC: 1540 AN: 21240

East Asian (EAS) AF: 0.105 AC: 3524 AN: 33622

South Asian (SAS) AF: 0.0526 AC: 3628 AN: 68966

European-Finnish (FIN) AF: 0.0727 AC: 3014 AN: 41464

Middle Eastern (MID) AF: 0.0939 AC: 391 AN: 4164

European-Non Finnish (NFE) AF: 0.0647 AC: 46791 AN: 722650

Other (OTH) AF: 0.0749 AC: 3268 AN: 43640

⚠️ 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: 0.00209 AC: 274 AN: 131268 Hom.: 3 Cov.: 0 AF XY: 0.00205 AC XY: 130 AN XY: 63348

African (AFR) AF: 0.00392 AC: 145 AN: 36944

American (AMR) AF: 0.00287 AC: 38 AN: 13244

Ashkenazi Jewish (ASJ) AF: 0.000648 AC: 2 AN: 3088

East Asian (EAS) AF: 0.00154 AC: 7 AN: 4550

South Asian (SAS) AF: 0.000503 AC: 2 AN: 3980

European-Finnish (FIN) AF: 0.00192 AC: 14 AN: 7308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.000995 AC: 59 AN: 59296

Other (OTH) AF: 0.00381 AC: 7 AN: 1836

Alfa AF: 0.0437 Hom.: 288

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

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;