19-49851455-G-T

Variant names:

• chr19-49851455-G-T
• rs1211868002
• ENST00000391842.6:c.127G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000391842.6(PTOV1):​c.127G>T​(p.Gly43Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,221,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PTOV1 ENST00000391842.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.384
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27157253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTOV1	NM_001305105.2	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 13		NP_001292034.1
PTOV1	NM_001394010.1	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 12		NP_001380939.1
PTOV1	NM_017432.5	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 13		NP_059128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTOV1	ENST00000391842.6	c.127G>T	p.Gly43Cys	missense_variant	Exon 1 of 12	5		ENSP00000375717.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151060 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000290 AC: 31 AN: 1070534 Hom.: 0 Cov.: 32 AF XY: 0.0000297 AC XY: 15 AN XY: 505798

African (AFR) AF: 0.00 AC: 0 AN: 22478

American (AMR) AF: 0.00 AC: 0 AN: 8068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13838

East Asian (EAS) AF: 0.00 AC: 0 AN: 25910

South Asian (SAS) AF: 0.00 AC: 0 AN: 19548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2878

European-Non Finnish (NFE) AF: 0.0000339 AC: 31 AN: 914044

Other (OTH) AF: 0.00 AC: 0 AN: 42902

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151060 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73746

African (AFR) AF: 0.00 AC: 0 AN: 41194

American (AMR) AF: 0.00 AC: 0 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67618

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127G>T (p.G43C) 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 127, causing the glycine (G) at amino acid position 43 to be replaced by a cysteine (C). 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	0.28
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.47	T;.;.
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		0.38
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.3	N;.;.
REVEL	Benign	0.097
Sift	Benign	0.12	T;.;.
Sift4G	Benign	0.061	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.37
MutPred		0.18		Loss of MoRF binding (P = 0.0779);Loss of MoRF binding (P = 0.0779);Loss of MoRF binding (P = 0.0779);
MVP		0.21
MPC		0.15
ClinPred		0.66	D
GERP RS		2.4
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.16
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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: rs1211868002; hg19: chr19-50354712;