chr15-41309848-A-G

Position:

chr15-41309848-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_007280.2(OIP5):c.596T>C(p.Leu199Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000626 in 1,596,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

OIP5
NM_007280.2 missense, splice_region

Scores

Splicing: ADA: 0.4353

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.70

Variant links:

Genes affected

OIP5 (HGNC:20300): (Opa interacting protein 5) The protein encoded by this gene localizes to centromeres, where it is essential for recruitment of CENP-A through the mediator Holliday junction recognition protein. Expression of this gene is upregulated in several cancers, making it a putative therapeutic target. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

OIP5 links:

OIP5-AS1 (HGNC:43563): (OIP5 antisense RNA 1) This is a conserved gene that produces a long non-coding RNA that maintains cell proliferation in embryonic stem cells. This RNA can bind to and negatively regulate the activity of multiple cellular RNAs and microRNAs, including cyclin G associated kinase and ELAV like RNA binding protein 1. [provided by RefSeq, Dec 2017]

OIP5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
OIP5	NM_007280.2 linkuse as main transcript	c.596T>C	p.Leu199Pro	missense_variant, splice_region_variant	5/5	ENST00000220514.8
OIP5-AS1	NR_152821.1 linkuse as main transcript	n.292+1007A>G		intron_variant, non_coding_transcript_variant
OIP5	NM_001317860.2 linkuse as main transcript	c.473T>C	p.Leu158Pro	missense_variant, splice_region_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OIP5	ENST00000220514.8 linkuse as main transcript	c.596T>C	p.Leu199Pro	missense_variant, splice_region_variant	5/5	1	NM_007280.2	P1
OIP5-AS1	ENST00000707047.1 linkuse as main transcript	n.523+1007A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248480

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134410

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1444064

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719464

show subpopulations

Gnomad4 AFR exome

AF:

0.0000906

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

AF:

0.0000460

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.596T>C (p.L199P) alteration is located in exon 5 (coding exon 5) of the OIP5 gene. This alteration results from a T to C substitution at nucleotide position 596, causing the leucine (L) at amino acid position 199 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MutPred

0.67

Loss of helix (P = 3e-04);

MVP

0.46

MPC

0.47

ClinPred

0.96

GERP RS

5.1

Varity_R

0.76

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.44

dbscSNV1_RF

Benign

0.49

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over