chr2-55636238-C-G

Variant names:

• chr2-55636238-C-G
• rs1256655826
• NM_033109.5:c.2351G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_033109.5(PNPT1):​c.2351G>C​(p.Ter784Serext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,423,200 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: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PNPT1 NM_033109.5 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• Publications: 0 publications found

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]

PNPT1 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia type 25

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 70

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_033109.5 Downstream stopcodon found after 790 codons.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033109.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	NM_033109.5	MANE Select	c.2351G>C	p.Ter784Serext*?	stop_lost	Exon 28 of 28	NP_149100.2	Q8TCS8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.2351G>C	p.Ter784Serext*?	stop_lost	Exon 28 of 28	ENSP00000400646.2	Q8TCS8
	PNPT1	ENST00000917025.1		c.2369G>C	p.Ter790Serext*?	stop_lost	Exon 28 of 28	ENSP00000587084.1
	PNPT1	ENST00000867135.1		c.2348G>C	p.Ter783Serext*?	stop_lost	Exon 28 of 28	ENSP00000537194.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1423200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707184

African (AFR) AF: 0.00 AC: 0 AN: 32250

American (AMR) AF: 0.00 AC: 0 AN: 40130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088246

Other (OTH) AF: 0.00 AC: 0 AN: 58750

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.84
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		2.0
Vest4		0.0060
GERP RS		3.1
Mutation Taster		=74/126	disease causing

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: rs1256655826; hg19: chr2-55863373;