2-55647357-G-C

Variant names:

• chr2-55647357-G-C
• rs374698153
• NM_033109.5:c.1592C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_033109.5(PNPT1):​c.1592C>G​(p.Thr531Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,604,756 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 7.40
• Publications: 1 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, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 2-55647357-G-C is Pathogenic according to our data. Variant chr2-55647357-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209184.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	NM_033109.5	MANE Select	c.1592C>G	p.Thr531Arg	missense	Exon 19 of 28	NP_149100.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.1592C>G	p.Thr531Arg	missense	Exon 19 of 28	ENSP00000400646.2
	PNPT1	ENST00000260604.8	TSL:5	n.*1147C>G		non_coding_transcript_exon	Exon 18 of 27	ENSP00000260604.4
	PNPT1	ENST00000415374.5	TSL:5	n.1592C>G		non_coding_transcript_exon	Exon 19 of 29	ENSP00000393953.1

Frequencies

GnomAD3 genomes AF: 0.0000791 AC: 12 AN: 151782 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 249564 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000984 AC: 143 AN: 1452974 Hom.: 0 Cov.: 30 AF XY: 0.0000927 AC XY: 67 AN XY: 722620

African (AFR) AF: 0.0000300 AC: 1 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 44030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 84240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1107258

Other (OTH) AF: 0.000134 AC: 8 AN: 59916

GnomAD4 genome AF: 0.0000791 AC: 12 AN: 151782 Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7 AN XY: 74124

African (AFR) AF: 0.0000242 AC: 1 AN: 41286

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67954

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000675 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PNPT1-related disorder Pathogenic:3

Jul 11, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Moderate, PM1, PM2

Oct 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PNPT1 c.1592C>G (p.Thr531Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249564 control chromosomes (gnomAD). c.1592C>G has been reported in the literature in individuals affected with features of Combined oxidative phosphorylation deficiency or with severe hearing loss (e.g. Rius_2019, Pennisi_2022, Cloney_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31752325, 33199448, 34740920, 36147510). ClinVar contains an entry for this variant (Variation ID: 209184). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PS3, PP3

not provided Pathogenic:1 Uncertain:2

Feb 02, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the heterozygous state in a patient with global developmental delay, intellectual disability, feeding difficulties, irritability, microcephaly, and dystonia who also harbored a second PNPT1 gene variant; the phase of the variants is unknown (PMID: 31752325); Observed in trans with variant of uncertain significance in the PNPT1 gene in an individual with encephalopathy, developmental delay, and hearing loss (PMID: 33199448); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31752325, 36147510, 34740920, 33199448)

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 531 of the PNPT1 protein (p.Thr531Arg). This variant is present in population databases (rs374698153, gnomAD 0.004%). This missense change has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 31752325, 33199448; external communication). ClinVar contains an entry for this variant (Variation ID: 209184). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PNPT1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Combined oxidative phosphorylation defect type 13 Pathogenic:2

Feb 23, 2015

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it three times in our laboratory in trans with another variant in affacted individuals: a 4-year-old male[with A507S] with global delays, speech articulation disorder, hypotonia; a 6-year-old male [with A507S] with spastic paraplegia, intellectual disability, anosmia, dysphagia, similarly affected sib (who is also compound heterozygous); an 18-year-old male [with V509I] with profound intellectual disability, severe bilateral hearing loss, hypotonia, dysmorphisms, short stature, microcephaly, hyperextensibility, myopia, cataract, congenital heart disease, fused kidneys, small testicles, type II diabetes, immunodeficiency (healthy sib NOT compound heterozygous)

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Thr531Arg variant in PNPT1 has been identified in the compound heterozygous state by our project in one individual with Combined Oxidative Phosphorylation Deficiency (COPD). The p.Thr531Arg variant has not been reported in the literature, but it has been reported in ClinVar (Variant ID: 209184). Baylor Laboratory reported this variant in 3 probands, however only 1/3 fit the current known clinical spectrum for PNPT1. Functional evidence (PNPase Western Blot, spectrophotometric enzyme assays, Dipstick assays, OXPHOS western blot) supports a pathogenic role for this variant and is consistent with other pathogenic variants (7 publications to date). The spectrophotometric enzyme assays conducted on fibroblasts were normal, which has been observed in other PNPT1- related cases including the one published in EJHG (Alodaib, A., et al. 2016) and others (Vedrenne, V., et al. 2012, Sato, R., et al. 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.

Autosomal recessive nonsyndromic hearing loss 70 Pathogenic:1

Mar 08, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Uncertain:1

Jul 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1592C>G (p.T531R) alteration is located in exon 19 (coding exon 19) of the PNPT1 gene. This alteration results from a C to G substitution at nucleotide position 1592, causing the threonine (T) at amino acid position 531 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.75
MPC		0.66
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374698153; hg19: chr2-55874492;