2-147943530-GAAAAA-GAAA

Position:

• chr2-147943530-GAAAAA-GAAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_181741.4(ORC4):​c.763-10_763-9del variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.108

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 403281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC4	NM_181741.4	c.763-10_763-9del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000392857.10	NP_859525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10	c.763-10_763-9del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_181741.4	ENSP00000376597	P1

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

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

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.0725

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.0526

Gnomad4 FIN exome AF: 0.0727

Gnomad4 NFE exome AF: 0.0647

Gnomad4 OTH exome AF: 0.0749

GnomAD4 genome AF: 0.00209 AC: 274 AN: 131268 Hom.: 3 Cov.: 0 AF XY: 0.00205 AC XY: 130 AN XY: 63348

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.000648

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000503

Gnomad4 FIN AF: 0.00192

Gnomad4 NFE AF: 0.000995

Gnomad4 OTH AF: 0.00381

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs66919703; hg19: chr2-148701099;