chr19-49851410-G-A

Variant names:

• chr19-49851410-G-A
• rs989773452
• ENST00000391842.6:c.82G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000391842.6(PTOV1):​c.82G>A​(p.Val28Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,049,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTOV1 ENST00000391842.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.342
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06645185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTOV1	NM_001305105.2	c.82G>A	p.Val28Met	missense_variant	Exon 1 of 13		NP_001292034.1
PTOV1	NM_001394010.1	c.82G>A	p.Val28Met	missense_variant	Exon 1 of 12		NP_001380939.1
PTOV1	NM_017432.5	c.82G>A	p.Val28Met	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.82G>A	p.Val28Met	missense_variant	Exon 1 of 12	5		ENSP00000375717.1

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 148922 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000246

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 46 AN: 1049228 Hom.: 0 Cov.: 32 AF XY: 0.0000666 AC XY: 33 AN XY: 495600

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000461 AC: 1 AN: 21670

American (AMR) AF: 0.00 AC: 0 AN: 7360

Ashkenazi Jewish (ASJ) AF: 0.0000782 AC: 1 AN: 12786

East Asian (EAS) AF: 0.0000418 AC: 1 AN: 23948

South Asian (SAS) AF: 0.0000515 AC: 1 AN: 19432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2746

European-Non Finnish (NFE) AF: 0.0000400 AC: 36 AN: 900198

Other (OTH) AF: 0.000146 AC: 6 AN: 41180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000134 AC: 2 AN: 149024 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72672

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000245 AC: 1 AN: 40752

American (AMR) AF: 0.00 AC: 0 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67020

Other (OTH) AF: 0.00 AC: 0 AN: 2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82G>A (p.V28M) alteration is located in exon 1 (coding exon 1) of the PTOV1 gene. This alteration results from a G to A substitution at nucleotide position 82, causing the valine (V) at amino acid position 28 to be replaced by a methionine (M). 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	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.020	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.44	T;.;.
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		-0.34
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	0.24	N;.;.
REVEL	Benign	0.0090
Sift	Benign	0.10	T;.;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.063
MVP		0.12
MPC		0.11
ClinPred		0.053	T
GERP RS		-1.9
PromoterAI		0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.025
gMVP		0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs989773452; hg19: chr19-50354667;