rs143712760

chr2-55647430-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_033109.5(PNPT1):c.1519G>T(p.Ala507Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,608,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:1
• Conservation: PhyloP100: 7.36

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_033109.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-55647430-C-A is Pathogenic according to our data. Variant chr2-55647430-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215010.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, Likely_pathogenic=4, Uncertain_significance=1}. Variant chr2-55647430-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-55647430-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPT1	NM_033109.5	c.1519G>T	p.Ala507Ser	missense_variant	19/28	ENST00000447944.7
PNPT1	XM_005264629.3	c.1279G>T	p.Ala427Ser	missense_variant	19/28
PNPT1	XM_017005172.2	c.1279G>T	p.Ala427Ser	missense_variant	18/27
PNPT1	XM_047446161.1	c.*51G>T		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPT1	ENST00000447944.7	c.1519G>T	p.Ala507Ser	missense_variant	19/28	1	NM_033109.5	P1

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151956 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 250814 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000325 AC: 473 AN: 1456098 Hom.: 0 Cov.: 30 AF XY: 0.000334 AC XY: 242 AN XY: 724428

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.000257 AC: 39 AN: 151956 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 74220

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000395 Hom.: 1

Bravo AF: 0.000291

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000222 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined oxidative phosphorylation defect type 13 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine (exon 19). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (60 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (RNase PH C domain; PMID: 31752325) (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple patients with PNPT1-related disorders (ClinVar, PMID: 30046113; 30831263; 25457163; 31752325) (P) 1001 - Strong functional evidence supporting abnormal protein function. Functional studies performed on fibroblast in a compound heterozygous patient showed reduced PNPase expression (PMID: 30046113) (P) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease.* (P) 1206 - Variant is paternally inherited.* (N) *Whole genome TRIO analysis was performed at the Garvan Institute under research settings. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.26; 3Cnet: 0.64). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000215010 / PMID: 25457163). A different missense change at the same codon (p.Ala507Gly) has been reported to be associated with PNPT1 related disorder (PMID: 32020600). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it twice in our laboratory in trans with another variant in affacted individuals: a 4-year-old male with global delays, speech articulation disroder, hypotonia; a 6-year-old male with spastic paraplegia, intellectual disability, anosmia, dysphagia, similarly affected sib (who is also compound heterozygous). Heterozygotes would be expected to be asymptomatic carriers. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 507 of the PNPT1 protein (p.Ala507Ser). This variant is present in population databases (rs143712760, gnomAD 0.05%). This missense change has been observed in individual(s) with PNPT1-related conditions (PMID: 25326635, 25457163, 30831263, 31752325, 32313153). 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: 215010). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28594066, 26016801, 28645153, 30244537, 30046113, 30831263, 31752325, 25457163, 32313153, 31694722, 33726816, 34440436, 34426522, 35012964, 30029642, 33199448, 36147510) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PNPT1: PP1:Strong, PM2, PM3, PM5:Supporting -

Spinocerebellar ataxia type 25 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2018

- -

Autosomal recessive nonsyndromic hearing loss 70 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 08, 2022

- -

Neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Apr 09, 2019

- -

Autosomal recessive nonsyndromic hearing loss 70;C4706283:Combined oxidative phosphorylation defect type 13 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Kids Research, The Children's Hospital at Westmead

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Benign	0.060	T
Sift4G	Benign	0.098	T
Polyphen		0.88	P
Vest4		0.93
MVP		0.56
MPC		0.42
ClinPred		0.23	T
GERP RS		5.5
Varity_R		0.34
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs143712760; hg19: chr2-55874565;