2-55636238-C-A

Position:

• chr2-55636238-C-A

Variant summary

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

The NM_033109.5(PNPT1):​c.2351G>T​(p.Ter784Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNPT1 NM_033109.5 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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: Stoplost variant in NM_033109.5 Downstream stopcodon found after 51 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPT1	NM_033109.5	c.2351G>T	p.Ter784Leuext*?	stop_lost	28/28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3	c.2111G>T	p.Ter704Leuext*?	stop_lost	28/28		XP_005264686.1
PNPT1	XM_017005172.2	c.2111G>T	p.Ter704Leuext*?	stop_lost	27/27		XP_016860661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7	c.2351G>T	p.Ter784Leuext*?	stop_lost	28/28	1	NM_033109.5	ENSP00000400646.2
PNPT1	ENST00000260604.8	n.*1893G>T		non_coding_transcript_exon_variant	27/27	5		ENSP00000260604.4
PNPT1	ENST00000415374.5	n.2351G>T		non_coding_transcript_exon_variant	28/29	5		ENSP00000393953.1
PNPT1	ENST00000260604.8	n.*1893G>T		3_prime_UTR_variant	27/27	5		ENSP00000260604.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1423186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

GeneDx

Dec 08, 2023

Stop codon loss and change to a Leu codon, leading to protein extension and the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	15
DANN	Benign	0.55
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.0060
GERP RS		3.1

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: rs1256655826; hg19: chr2-55863373;