2-55636298-T-C

Variant names:

• chr2-55636298-T-C
• rs376543538
• NM_033109.5:c.2291A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033109.5(PNPT1):​c.2291A>G​(p.Asn764Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.425
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032690555).

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.2291A>G	p.Asn764Ser	missense	Exon 28 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.2291A>G	p.Asn764Ser	missense	Exon 28 of 28	ENSP00000400646.2	Q8TCS8
	PNPT1	ENST00000917025.1		c.2309A>G	p.Asn770Ser	missense	Exon 28 of 28	ENSP00000587084.1
	PNPT1	ENST00000867135.1		c.2288A>G	p.Asn763Ser	missense	Exon 28 of 28	ENSP00000537194.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111846

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.6
DANN	Benign	0.92
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.42
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.063
Sift	Benign	0.28	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.014
MutPred		0.18		Gain of phosphorylation at N764 (P = 0.0104)
MVP		0.32
MPC		0.11
ClinPred		0.21	T
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.080
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs376543538; hg19: chr2-55863433;