2-55636240-CT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_033109.5(PNPT1):c.2348del(p.Gln783ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q783Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PNPT1 NM_033109.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.509

Genes affected

PNPT1 (HGNC:23166): (polyribonucleotide nucleotidyltransferase 1) The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 783 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPT1	NM_033109.5	c.2348del	p.Gln783ArgfsTer6	frameshift_variant	28/28	ENST00000447944.7
PNPT1	XM_005264629.3	c.2108del	p.Gln703ArgfsTer6	frameshift_variant	28/28
PNPT1	XM_017005172.2	c.2108del	p.Gln703ArgfsTer6	frameshift_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPT1	ENST00000447944.7	c.2348del	p.Gln783ArgfsTer6	frameshift_variant	28/28	1	NM_033109.5	P1
PNPT1	ENST00000415374.5	c.2348del	p.Gln783ArgfsTer6	frameshift_variant, NMD_transcript_variant	28/29	5
PNPT1	ENST00000260604.8	c.*1890del		3_prime_UTR_variant, NMD_transcript_variant	27/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

ClinVar contains an entry for this variant (Variation ID: 1476883). This variant has not been reported in the literature in individuals affected with PNPT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the PNPT1 gene (p.Gln783Argfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the PNPT1 protein and extend the protein by 4 additional amino acid residues. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1391187004; hg19: chr2-55863375;