rs199686309

Variant names:

• chr7-104166851-T-A
• rs199686309
• NM_002553.4:c.911A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-104166851-T-A
• chr7-104166851-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002553.4(ORC5):​c.911A>T​(p.Tyr304Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y304C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ORC5 NM_002553.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.49

Genes affected

ORC5 (HGNC:8491): (origin recognition complex subunit 5) 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. The protein encoded by this gene is a subunit of the ORC complex. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2832713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORC5	NM_002553.4	c.911A>T	p.Tyr304Phe	missense_variant	Exon 10 of 14	ENST00000297431.9	NP_002544.1
ORC5	XM_047420431.1	c.*57A>T		3_prime_UTR_variant	Exon 8 of 8		XP_047276387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC5	ENST00000297431.9	c.911A>T	p.Tyr304Phe	missense_variant	Exon 10 of 14	1	NM_002553.4	ENSP00000297431.4
ORC5	ENST00000422497.5	n.*844A>T		non_coding_transcript_exon_variant	Exon 11 of 15	2		ENSP00000393208.1
ORC5	ENST00000422497.5	n.*844A>T		3_prime_UTR_variant	Exon 11 of 15	2		ENSP00000393208.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458956 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725874

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.0034
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.12
Sift	Benign	0.41	T
Sift4G	Benign	0.73	T
Polyphen		0.0030	B
Vest4		0.53
MutPred		0.51		Gain of helix (P = 0.0325);
MVP		0.34
MPC		0.071
ClinPred		0.76	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs199686309; hg19: chr7-103807299;