19-49851350-C-T

Variant names:

• chr19-49851350-C-T
• rs868811720
• ENST00000391842.6:c.22C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000391842.6(PTOV1):​c.22C>T​(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,098,286 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. P8L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (3 hom.)
• Consequence: PTOV1 ENST00000391842.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024394542).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTOV1	NM_001305105.2	c.22C>T	p.Pro8Ser	missense_variant	Exon 1 of 13		NP_001292034.1
PTOV1	NM_001394010.1	c.22C>T	p.Pro8Ser	missense_variant	Exon 1 of 12		NP_001380939.1
PTOV1	NM_017432.5	c.22C>T	p.Pro8Ser	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.22C>T	p.Pro8Ser	missense_variant	Exon 1 of 12	5		ENSP00000375717.1

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 380 AN: 148246 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00899

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000535

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: 0.0000451

Gnomad OTH AF: 0.000982

GnomAD2 exomes AF: 0.00 AC: 0 AN: 6 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 182 AN: 949932 Hom.: 3 Cov.: 32 AF XY: 0.000168 AC XY: 75 AN XY: 446146

African (AFR) AF: 0.00861 AC: 161 AN: 18690

American (AMR) AF: 0.000677 AC: 3 AN: 4430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8874

East Asian (EAS) AF: 0.00 AC: 0 AN: 12610

South Asian (SAS) AF: 0.00 AC: 0 AN: 18384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12222

Middle Eastern (MID) AF: 0.000453 AC: 1 AN: 2208

European-Non Finnish (NFE) AF: 0.00000477 AC: 4 AN: 837898

Other (OTH) AF: 0.000376 AC: 13 AN: 34616

GnomAD4 genome AF: 0.00257 AC: 381 AN: 148354 Hom.: 1 Cov.: 31 AF XY: 0.00250 AC XY: 181 AN XY: 72394

African (AFR) AF: 0.00898 AC: 368 AN: 40958

American (AMR) AF: 0.000534 AC: 8 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000451 AC: 3 AN: 66472

Other (OTH) AF: 0.000972 AC: 2 AN: 2058

Alfa AF: 0.00192 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22C>T (p.P8S) 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 22, causing the proline (P) at amino acid position 8 to be replaced by a serine (S). 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	0.21
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.57	T;.;.
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.024	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		1.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.60	N;.;.
REVEL	Benign	0.045
Sift	Benign	0.11	T;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.036	B;B;B
Vest4		0.10
MutPred		0.29		Gain of phosphorylation at P8 (P = 0.0019);Gain of phosphorylation at P8 (P = 0.0019);Gain of phosphorylation at P8 (P = 0.0019);
MVP		0.20
MPC		0.44
ClinPred		0.54	D
GERP RS		3.5
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.094
gMVP		0.23
Mutation Taster		=93/7	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: rs868811720; hg19: chr19-50354607;