dbSNP rs1051308974: PNPT1:p.Ser782Phe (chr2-55636244-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_033109.5(PNPT1):c.2345C>T(p.Ser782Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,453,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S782C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PNPT1
NM_033109.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.77

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity PNPT1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14620155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPT1	NM_033109.5 link	c.2345C>T	p.Ser782Phe	missense_variant	Exon 28 of 28	ENST00000447944.7	NP_149100.2	Q8TCS8
PNPT1	XM_005264629.3 link	c.2105C>T	p.Ser702Phe	missense_variant	Exon 28 of 28		XP_005264686.1
PNPT1	XM_017005172.2 link	c.2105C>T	p.Ser702Phe	missense_variant	Exon 27 of 27		XP_016860661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7 link	c.2345C>T	p.Ser782Phe	missense_variant	Exon 28 of 28	1	NM_033109.5	ENSP00000400646.2		Q8TCS8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453314

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

722282

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000356

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.0041

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

Eigen

Benign

0.046

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.024

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.76

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.76

REVEL

Benign

0.13

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0030

Polyphen

0.30

Vest4

0.33

MutPred

0.24

Loss of phosphorylation at S782 (P = 0.0074);

MVP

0.49

MPC

0.22

ClinPred

0.69

GERP RS

5.1

Varity_R

0.11

gMVP

0.31

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over