Genetic Variant NM_181741.4:c.763-4T>G (chr2-147943526-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_181741.4(ORC4):c.763-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000418 in 1,505,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ORC4
NM_181741.4 splice_region, intron

Scores

Splicing: ADA: 0.0001233

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 1.09

Publications

0 publications found

Variant links:

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

ORC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORC4	NM_181741.4 link	c.763-4T>G		splice_region_variant, intron_variant	Intron 9 of 13	ENST00000392857.10	NP_859525.1	O43929-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10 link	c.763-4T>G		splice_region_variant, intron_variant	Intron 9 of 13	1	NM_181741.4	ENSP00000376597.5		O43929-1

Frequencies

GnomAD3 genomes

AF:

0.0000414

AC:

AN:

120788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000168

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000343

Gnomad OTH

AF:

0.000631

GnomAD2 exomes

AF:

0.000120

AC:

AN:

192252

AF XY:

0.000134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000460

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000806

Gnomad OTH exome

AF:

0.000402

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1384700

Hom.:

Cov.:

AF XY:

0.0000519

AC XY:

AN XY:

693076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31928

American (AMR)

AF:

0.000295

AC:

AN:

44048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25504

East Asian (EAS)

AF:

0.00

AC:

AN:

39212

South Asian (SAS)

AF:

0.0000949

AC:

AN:

84260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51324

Middle Eastern (MID)

AF:

0.000536

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.0000230

AC:

AN:

1044972

Other (OTH)

AF:

0.000173

AC:

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000414

AC:

AN:

120788

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

59070

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27838

American (AMR)

AF:

0.000168

AC:

AN:

11902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2966

East Asian (EAS)

AF:

0.00

AC:

AN:

3876

South Asian (SAS)

AF:

0.00

AC:

AN:

4152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000343

AC:

AN:

58326

Other (OTH)

AF:

0.000631

AC:

AN:

1584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ORC4-related disorder

Benign:1

Dec 18, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.6

(source)

DANN

Benign

0.79

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.0060

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

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NM_181741.4:c.763-4T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over