rs563641001

Variant names:

• chr19-49851348-C-A
• rs563641001
• ENST00000391842.6:c.20C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000391842.6(PTOV1):​c.20C>A​(p.Ala7Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,095,420 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. A7V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0084 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00068 (12 hom.)
• Consequence: PTOV1 ENST00000391842.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.242
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002914995).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00844 (1252/148408) while in subpopulation AFR AF = 0.0292 (1194/40928). AF 95% confidence interval is 0.0278. There are 14 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTOV1	NM_001305105.2	c.20C>A	p.Ala7Asp	missense_variant	Exon 1 of 13		NP_001292034.1
PTOV1	NM_001394010.1	c.20C>A	p.Ala7Asp	missense_variant	Exon 1 of 12		NP_001380939.1
PTOV1	NM_017432.5	c.20C>A	p.Ala7Asp	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.20C>A	p.Ala7Asp	missense_variant	Exon 1 of 12	5		ENSP00000375717.1

Frequencies

GnomAD3 genomes AF: 0.00842 AC: 1249 AN: 148298 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00261

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.00739

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

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.000682 AC: 646 AN: 947012 Hom.: 12 Cov.: 32 AF XY: 0.000580 AC XY: 258 AN XY: 444610

African (AFR) AF: 0.0301 AC: 559 AN: 18594

American (AMR) AF: 0.00300 AC: 13 AN: 4338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8786

East Asian (EAS) AF: 0.00 AC: 0 AN: 12232

South Asian (SAS) AF: 0.00 AC: 0 AN: 18346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11878

Middle Eastern (MID) AF: 0.000910 AC: 2 AN: 2198

European-Non Finnish (NFE) AF: 0.0000144 AC: 12 AN: 836204

Other (OTH) AF: 0.00174 AC: 60 AN: 34436

GnomAD4 genome AF: 0.00844 AC: 1252 AN: 148408 Hom.: 14 Cov.: 31 AF XY: 0.00825 AC XY: 597 AN XY: 72392

African (AFR) AF: 0.0292 AC: 1194 AN: 40928

American (AMR) AF: 0.00260 AC: 39 AN: 14986

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9408

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0000300 AC: 2 AN: 66556

Other (OTH) AF: 0.00730 AC: 15 AN: 2054

Alfa AF: 0.00687 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20C>A (p.A7D) alteration is located in exon 1 (coding exon 1) of the PTOV1 gene. This alteration results from a C to A substitution at nucleotide position 20, causing the alanine (A) at amino acid position 7 to be replaced by an aspartic acid (D). 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	0.64
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.50	T;.;.
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		-0.24
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.63	N;.;.
REVEL	Benign	0.073
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.96	P;P;P
Vest4		0.24
MutPred		0.17		Loss of methylation at R5 (P = 0.064);Loss of methylation at R5 (P = 0.064);Loss of methylation at R5 (P = 0.064);
MVP		0.36
MPC		0.57
ClinPred		0.55	D
GERP RS		3.5
PromoterAI		0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.57
gMVP		0.38
Mutation Taster		=97/3	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: rs563641001; hg19: chr19-50354605; COSMIC: COSV109411865; COSMIC: COSV109411865;