2-147943530-GAAAAA-GAAAA

Position:

• chr2-147943530-GAAAAA-GAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_181741.4(ORC4):​c.763-9del variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 -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 id is 403280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-147943530-GA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

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

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

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

Gnomad4 AFR exome AF: 0.469

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.455

Gnomad4 EAS exome AF: 0.470

Gnomad4 SAS exome AF: 0.445

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.438

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

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.505

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.440

Gnomad4 OTH AF: 0.511

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meier-Gorlin syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 09, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2020

- -

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;