2-147943530-GAAAAA-GA

Position:

• chr2-147943530-GAAAAA-GA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_181741.4(ORC4):​c.763-12_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 0.000236 in 1,167,740 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ORC4 NM_181741.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.120

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000264 (274/1036452) while in subpopulation AMR AF= 0.000498 (19/38122). AF 95% confidence interval is 0.000326. There are 0 homozygotes in gnomad4_exome. There are 127 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC4	NM_181741.4	c.763-12_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.763-12_763-9del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_181741.4	ENSP00000376597	P1

Frequencies

GnomAD3 genomes AF: 0.0000152 AC: 2 AN: 131288 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000337

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000264 AC: 274 AN: 1036452 Hom.: 0 AF XY: 0.000239 AC XY: 127 AN XY: 531060

Gnomad4 AFR exome AF: 0.000292

Gnomad4 AMR exome AF: 0.000498

Gnomad4 ASJ exome AF: 0.000179

Gnomad4 EAS exome AF: 0.000138

Gnomad4 SAS exome AF: 0.000180

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.000267

Gnomad4 OTH exome AF: 0.000262

GnomAD4 genome AF: 0.0000152 AC: 2 AN: 131288 Hom.: 0 Cov.: 0 AF XY: 0.0000158 AC XY: 1 AN XY: 63336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000337

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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;