2-55636253-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033109.5(PNPT1):c.2336C>T(p.Ser779Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,608,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. S779P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20759699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPT1	NM_033109.5	c.2336C>T	p.Ser779Leu	missense_variant	28/28	ENST00000447944.7
PNPT1	XM_005264629.3	c.2096C>T	p.Ser699Leu	missense_variant	28/28
PNPT1	XM_017005172.2	c.2096C>T	p.Ser699Leu	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPT1	ENST00000447944.7	c.2336C>T	p.Ser779Leu	missense_variant	28/28	1	NM_033109.5	P1
PNPT1	ENST00000415374.5	c.2336C>T	p.Ser779Leu	missense_variant, NMD_transcript_variant	28/29	5
PNPT1	ENST00000260604.8	c.*1878C>T		3_prime_UTR_variant, NMD_transcript_variant	27/27	5

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151882 Hom.: 0 Cov.: 33

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000564 AC: 14 AN: 248196 Hom.: 0 AF XY: 0.0000672 AC XY: 9 AN XY: 133930

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 167 AN: 1456530 Hom.: 0 Cov.: 32 AF XY: 0.000115 AC XY: 83 AN XY: 724304

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: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151882 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74176

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2022

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 779 of the PNPT1 protein (p.Ser779Leu). This variant is present in population databases (rs201880461, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PNPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1476968). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.16	B
Vest4		0.48
MVP		0.35
MPC		0.16
ClinPred		0.17	T
GERP RS		6.0
Varity_R		0.080
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs201880461; hg19: chr2-55863388;