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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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 ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	NM_033109.5	MANE Select	c.1528G>A	p.Ala510Thr	missense	Exon 19 of 28	NP_149100.2	Q8TCS8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.1528G>A	p.Ala510Thr	missense	Exon 19 of 28	ENSP00000400646.2	Q8TCS8
	PNPT1	ENST00000917025.1		c.1546G>A	p.Ala516Thr	missense	Exon 19 of 28	ENSP00000587084.1
	PNPT1	ENST00000867135.1		c.1528G>A	p.Ala510Thr	missense	Exon 19 of 28	ENSP00000537194.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined oxidative phosphorylation defect type 13 (1)

Computational scores

Source: dbNSFP v4.9

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;