rs1085307083

Variant names:

• chr2-147975958-T-C
• rs1085307083
• NM_181741.4:c.1A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_181741.4(ORC4):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000193 in 1,553,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ORC4 NM_181741.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.96
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 75 codons. Genomic position: 147972741. Lost 0.170 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-147975958-T-C is Pathogenic according to our data. Variant chr2-147975958-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 225427.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1A>G	p.Met1?	start_lost	Exon 2 of 14	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.1A>G	p.Met1?	start_lost	Exon 3 of 15	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.1A>G	p.Met1?	start_lost	Exon 4 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.1A>G	p.Met1?	start_lost	Exon 2 of 14	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.1A>G	p.Met1?	start_lost	Exon 2 of 15	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 2 of 14	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes AF: 0.00000775 AC: 1 AN: 129046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424170 Hom.: 0 Cov.: 24 AF XY: 0.00000141 AC XY: 1 AN XY: 710754

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

African (AFR) AF: 0.00 AC: 0 AN: 32866

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39450

South Asian (SAS) AF: 0.00 AC: 0 AN: 85508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078100

Other (OTH) AF: 0.00 AC: 0 AN: 59076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000775 AC: 1 AN: 129046 Hom.: 0 Cov.: 32 AF XY: 0.0000159 AC XY: 1 AN XY: 62852

African (AFR) AF: 0.00 AC: 0 AN: 30262

American (AMR) AF: 0.00 AC: 0 AN: 12646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3058

East Asian (EAS) AF: 0.000220 AC: 1 AN: 4540

South Asian (SAS) AF: 0.00 AC: 0 AN: 4216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62032

Other (OTH) AF: 0.00 AC: 0 AN: 1708

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Meier-Gorlin syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.020	T
PhyloP100		5.0
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.91
MutPred		0.96		Loss of MoRF binding (P = 0.1018)
MVP		0.82
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.57
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1085307083; hg19: chr2-148733527;