chr2-55647421-C-T

Variant names:

• chr2-55647421-C-T
• rs879255657
• NM_033109.5:c.1528G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_033109.5(PNPT1):​c.1528G>A​(p.Ala510Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A510P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36
• 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, 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_033109.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-55647421-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 253224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPT1	NM_033109.5	c.1528G>A	p.Ala510Thr	missense_variant	Exon 19 of 28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3	c.1288G>A	p.Ala430Thr	missense_variant	Exon 19 of 28		XP_005264686.1
PNPT1	XM_017005172.2	c.1288G>A	p.Ala430Thr	missense_variant	Exon 18 of 27		XP_016860661.1
PNPT1	XM_047446161.1	c.*60G>A		3_prime_UTR_variant	Exon 20 of 20		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7	c.1528G>A	p.Ala510Thr	missense_variant	Exon 19 of 28	1	NM_033109.5	ENSP00000400646.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 13 Uncertain:1

Jan 22, 2024

Institute of Human Genetics, University of Goettingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.1528G>A (p.(Ala510Thr)) in exon 19 of the PNPT1-gene is not found in the gnomAD database, it affects a moderately conserved nucleotide, a highly conserved amino acid within a protein domain and there is a small physicochemical difference between Ala and Thr. p.(Ala510Thr) is a missense mutation at an amino acid residue where another missense change determined to be pathogenic has been already described (p.Ala510Pro, PMID: 27759031). This variant has a pathogenic computational verdict based in silico prediction models. It was found in homozygous state in a patient with suspected mitochondriopathy. ACMG criteria used for classification: PM2_supp, PM5, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.090	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.74		Gain of sheet (P = 0.0344);
MVP		0.62
MPC		0.61
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.88
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs879255657; hg19: chr2-55874556;