chr2-55683831-C-T

Position:

• chr2-55683831-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000447944.7(PNPT1):​c.407G>A​(p.Arg136His) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PNPT1 ENST00000447944.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 6.89

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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-55683832-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1805654.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 2-55683831-C-T is Pathogenic according to our data. Variant chr2-55683831-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-55683831-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-55683831-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPT1	NM_033109.5	c.407G>A	p.Arg136His	missense_variant	5/28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3	c.167G>A	p.Arg56His	missense_variant	5/28		XP_005264686.1
PNPT1	XM_017005172.2	c.167G>A	p.Arg56His	missense_variant	4/27		XP_016860661.1
PNPT1	XM_047446161.1	c.407G>A	p.Arg136His	missense_variant	5/20		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7	c.407G>A	p.Arg136His	missense_variant	5/28	1	NM_033109.5	ENSP00000400646	P1
PNPT1	ENST00000415374.5	c.407G>A	p.Arg136His	missense_variant, NMD_transcript_variant	5/29	5		ENSP00000393953
PNPT1	ENST00000260604.8	c.407G>A	p.Arg136His	missense_variant, NMD_transcript_variant	5/27	5		ENSP00000260604
PNPT1	ENST00000429805.1	c.*55G>A		3_prime_UTR_variant, NMD_transcript_variant	3/6	3		ENSP00000411994

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251096 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461286 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation defect type 13 Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 30, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 136 of the PNPT1 protein (p.Arg136His). This variant is present in population databases (rs746356243, gnomAD 0.02%). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 28645153, 30046113, 33199448). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 587375). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PNPT1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28645153, 30046113, 31752325, 30244537, 33199448, 34758253, 37298184, 34498404, deLen-Ojeda2024[paper]) -

Inborn genetic diseases Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Mar 26, 2021

The c.407G>A (p.R136H) alteration is located in exon 5 (coding exon 5) of the PNPT1 gene. This alteration results from a G to A substitution at nucleotide position 407, causing the arginine (R) at amino acid position 136 to be replaced by a histidine (H). The in silico prediction for the p.R136H alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.95		Loss of phosphorylation at S137 (P = 0.1052);
MVP		0.76
MPC		0.69
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.87

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: rs746356243; hg19: chr2-55910966;