rs138876526

Variant names:

• chr2-147938178-C-T
• rs138876526
• NM_181741.4:c.1090G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_181741.4(ORC4):​c.1090G>A​(p.Val364Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,612,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.11
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008985847).
• BP6: Variant 2-147938178-C-T is Benign according to our data. Variant chr2-147938178-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436116.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00133 (203/152142) while in subpopulation AFR AF = 0.00318 (132/41514). AF 95% confidence interval is 0.00274. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	NM_181741.4	MANE Select	c.1090G>A	p.Val364Ile	missense	Exon 13 of 14	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.1090G>A	p.Val364Ile	missense	Exon 14 of 15	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.1090G>A	p.Val364Ile	missense	Exon 15 of 16	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.1090G>A	p.Val364Ile	missense	Exon 13 of 14	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.1090G>A	p.Val364Ile	missense	Exon 13 of 15	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.1090G>A	p.Val364Ile	missense	Exon 13 of 14	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 203 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000659 AC: 165 AN: 250442 AF XY: 0.000569

Gnomad AFR exome AF: 0.00353

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000725

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000807 AC: 1178 AN: 1460290 Hom.: 1 Cov.: 29 AF XY: 0.000776 AC XY: 564 AN XY: 726530

African (AFR) AF: 0.00398 AC: 133 AN: 33430

American (AMR) AF: 0.000515 AC: 23 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86220

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.000863 AC: 959 AN: 1110926

Other (OTH) AF: 0.000862 AC: 52 AN: 60302

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74390

African (AFR) AF: 0.00318 AC: 132 AN: 41514

American (AMR) AF: 0.00170 AC: 26 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 67980

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000784 Hom.: 0

Bravo AF: 0.00181

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000643 AC: 78

EpiCase AF: 0.000818

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	ORC4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.93	L
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.12
Sift	Benign	0.46	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.67
MPC		0.076
ClinPred		0.012	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.14
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138876526; hg19: chr2-148695747;