Genetic Variant PTOV1:p.Arg22Leu (chr19-49851393-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000391842.6(PTOV1):c.65G>T(p.Arg22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,174,120 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

PTOV1
ENST00000391842.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.97

Publications

0 publications found

Variant links:

Genes affected

PTOV1 (HGNC:9632): (PTOV1 extended AT-hook containing adaptor protein) This gene encodes a protein that was found to be overexpressed in prostate adenocarcinomas. The encoded protein was found to interact with the lipid raft protein flotillin-1 and shuttle it from the cytoplasm to the nucleus in a cell cycle dependent manner. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

PTOV1 links:

PTOV1-AS1 (HGNC:44174): (PTOV1 antisense RNA 1)

PTOV1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
PTOV1	NM_001305105.2 link	c.65G>T	p.Arg22Leu	missense_variant	Exon 1 of 13	NP_001292034.1	Q86YD1-1
PTOV1	NM_001394010.1 link	c.65G>T	p.Arg22Leu	missense_variant	Exon 1 of 12	NP_001380939.1
PTOV1	NM_017432.5 link	c.65G>T	p.Arg22Leu	missense_variant	Exon 1 of 13	NP_059128.2	Q86YD1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTOV1	ENST00000391842.6 link	c.65G>T	p.Arg22Leu	missense_variant	Exon 1 of 12	5		ENSP00000375717.1		Q86YD1-1

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

147906

Hom.:

Cov.:

show subpopulations

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:

0.0000300

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1026120

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

483920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20908

American (AMR)

AF:

0.00

AC:

AN:

6572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11802

East Asian (EAS)

AF:

0.00

AC:

AN:

21642

South Asian (SAS)

AF:

0.00

AC:

AN:

19092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2626

European-Non Finnish (NFE)

AF:

0.0000215

AC:

AN:

885392

Other (OTH)

AF:

0.00

AC:

AN:

39540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40402

American (AMR)

AF:

0.00

AC:

AN:

14970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3424

East Asian (EAS)

AF:

0.00

AC:

AN:

5016

South Asian (SAS)

AF:

0.00

AC:

AN:

4730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66698

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.65G>T (p.R22L) alteration is located in exon 1 (coding exon 1) of the PTOV1 gene. This alteration results from a G to T substitution at nucleotide position 65, causing the arginine (R) at amino acid position 22 to be replaced by a leucine (L). 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

Benign

0.18

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.018

T;T;T

Eigen

Benign

0.039

Eigen_PC

Benign

0.012

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.63

T;.;.

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

3.0

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.22

N;.;.

REVEL

Benign

0.26

Sift

Uncertain

0.018

D;.;.

Sift4G

Benign

0.29

T;T;T

Polyphen

0.96

D;D;D

Vest4

0.38

MutPred

0.27

Loss of methylation at R22 (P = 0.0109);Loss of methylation at R22 (P = 0.0109);Loss of methylation at R22 (P = 0.0109);

MVP

0.26

MPC

0.42

ClinPred

0.60

GERP RS

3.3

PromoterAI

0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.25

gMVP

0.39

Mutation Taster

=94/6

polymorphism

(source)

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

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chr19-49851393-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over