2-55636311-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033109.5(PNPT1):c.2278G>C(p.Val760Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05258295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPT1	NM_033109.5	c.2278G>C	p.Val760Leu	missense_variant	28/28	ENST00000447944.7
PNPT1	XM_005264629.3	c.2038G>C	p.Val680Leu	missense_variant	28/28
PNPT1	XM_017005172.2	c.2038G>C	p.Val680Leu	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPT1	ENST00000447944.7	c.2278G>C	p.Val760Leu	missense_variant	28/28	1	NM_033109.5	P1
PNPT1	ENST00000415374.5	c.2278G>C	p.Val760Leu	missense_variant, NMD_transcript_variant	28/29	5
PNPT1	ENST00000260604.8	c.*1820G>C		3_prime_UTR_variant, NMD_transcript_variant	27/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727176

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: 8.99e-7

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

Invitae

Jul 30, 2022

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 760 of the PNPT1 protein (p.Val760Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PNPT1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PNPT1 protein function. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.020
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.046
MutPred		0.27		Loss of MoRF binding (P = 0.0911);
MVP		0.20
MPC		0.14
ClinPred		0.29	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.24

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: rs1340851603; hg19: chr2-55863446;