2-147943530-GAAAAAA-GAAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

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

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 0)
  • Exomes 𝑓: 0.013 (0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-147943530-G-GA is Benign according to our data. Variant chr2-147943530-G-GA is described in ClinVar as Benign. ClinVar VariationId is 770872.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000396 (52/131276) while in subpopulation SAS AF = 0.00276 (11/3980). AF 95% confidence interval is 0.00155. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.763-9dupT		intron	N/A	NP_859525.1
	ORC4	NM_001190879.3		c.763-9dupT		intron	N/A	NP_001177808.1
	ORC4	NM_001374270.1		c.763-9dupT		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_763-8insT		intron	N/A	ENSP00000376597.5
	ORC4	ENST00000264169.6	TSL:5	c.763-9_763-8insT		intron	N/A	ENSP00000264169.2
	ORC4	ENST00000535373.5	TSL:5	c.763-9_763-8insT		intron	N/A	ENSP00000441953.1

Frequencies

GnomAD3 genomes AF: 0.000396 AC: 52 AN: 131258 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000657

Gnomad SAS AF: 0.00275

Gnomad FIN AF: 0.000547

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000472

Gnomad OTH AF: 0.00109

GnomAD2 exomes AF: 0.00580 AC: 977 AN: 168506 AF XY: 0.00585

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.00504

Gnomad EAS exome AF: 0.00419

Gnomad FIN exome AF: 0.00849

Gnomad NFE exome AF: 0.00599

Gnomad OTH exome AF: 0.00682

GnomAD4 exome AF: 0.0126 AC: 12966 AN: 1031142 Hom.: 0 Cov.: 0 AF XY: 0.0121 AC XY: 6375 AN XY: 528188

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

African (AFR) AF: 0.00619 AC: 148 AN: 23926

American (AMR) AF: 0.00505 AC: 192 AN: 38008

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 175 AN: 22200

East Asian (EAS) AF: 0.00487 AC: 176 AN: 36154

South Asian (SAS) AF: 0.00956 AC: 684 AN: 71528

European-Finnish (FIN) AF: 0.00760 AC: 331 AN: 43576

Middle Eastern (MID) AF: 0.00757 AC: 33 AN: 4360

European-Non Finnish (NFE) AF: 0.0143 AC: 10701 AN: 745908

Other (OTH) AF: 0.0116 AC: 526 AN: 45482

⚠️ 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: 0.000396 AC: 52 AN: 131276 Hom.: 0 Cov.: 0 AF XY: 0.000410 AC XY: 26 AN XY: 63356

African (AFR) AF: 0.0000541 AC: 2 AN: 36942

American (AMR) AF: 0.000151 AC: 2 AN: 13244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3088

East Asian (EAS) AF: 0.000659 AC: 3 AN: 4554

South Asian (SAS) AF: 0.00276 AC: 11 AN: 3980

European-Finnish (FIN) AF: 0.000547 AC: 4 AN: 7314

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

European-Non Finnish (NFE) AF: 0.000472 AC: 28 AN: 59294

Other (OTH) AF: 0.00109 AC: 2 AN: 1838

Alfa AF: 0.00469 Hom.: 288

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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;