19-49851344-C-T

Position:

• chr19-49851344-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000391842.6(PTOV1):​c.16C>T​(p.Arg6Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 941,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R6H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTOV1 ENST00000391842.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.668

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2269859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTOV1	NM_001394010.1	c.16C>T	p.Arg6Cys	missense_variant	1/12	ENST00000391842.6
PTOV1-AS1	NR_040037.1	n.109+224G>A		intron_variant, non_coding_transcript_variant
PTOV1	NR_130963.2	n.251+389C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTOV1	ENST00000391842.6	c.16C>T	p.Arg6Cys	missense_variant	1/12	5	NM_001394010.1	P1
PTOV1-AS1	ENST00000596521.1	n.109+224G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000213 AC: 2 AN: 941014 Hom.: 0 Cov.: 32 AF XY: 0.00000226 AC XY: 1 AN XY: 441612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000240

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.16C>T (p.R6C) alteration is located in exon 1 (coding exon 1) of the PTOV1 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the arginine (R) at amino acid position 6 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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;T
Eigen	Benign	0.035
Eigen_PC	Benign	0.0083
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.72	T;.;.
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.6	N;.;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.037	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.27
MutPred		0.27		Loss of methylation at R6 (P = 0.0211);Loss of methylation at R6 (P = 0.0211);Loss of methylation at R6 (P = 0.0211);
MVP		0.35
MPC		0.52
ClinPred		0.75	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.30
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2074236321; hg19: chr19-50354601;