19-49859918-A-T

Variant names:

• chr19-49859918-A-T
• rs1290646
• NM_001394010.1:c.1042-68A>T

Variant summary

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

The NM_001394010.1(PTOV1):​c.1042-68A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PTOV1 NM_001394010.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.886
• 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]

PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

PNKP Gene-Disease associations (from GenCC):

• ataxia - oculomotor apraxia type 4

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 2B2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 (BayesDel_noAF=-0.89).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394010.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTOV1	NM_001394010.1	MANE Select	c.1042-68A>T		intron	N/A	NP_001380939.1
	PTOV1	NM_001364747.2		c.1087-68A>T		intron	N/A	NP_001351676.1
	PTOV1	NM_001364749.2		c.1087-68A>T		intron	N/A	NP_001351678.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTOV1	ENST00000391842.6	TSL:5 MANE Select	c.1042-68A>T		intron	N/A	ENSP00000375717.1
	PTOV1	ENST00000599732.5	TSL:1	c.1042-68A>T		intron	N/A	ENSP00000469128.1
	PTOV1	ENST00000601675.5	TSL:1	c.1042-68A>T		intron	N/A	ENSP00000472816.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392404 Hom.: 0 Cov.: 23 AF XY: 0.00000144 AC XY: 1 AN XY: 695868

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

African (AFR) AF: 0.00 AC: 0 AN: 31958

American (AMR) AF: 0.00 AC: 0 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 39248

South Asian (SAS) AF: 0.00 AC: 0 AN: 84448

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050894

Other (OTH) AF: 0.00 AC: 0 AN: 57994

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.82
DANN	Benign	0.63
PhyloP100		-0.89
PromoterAI		0.0025	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1290646; hg19: chr19-50363175;