Genetic Variant PNPT1:c.-158G>T (chr2-55693981-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033109.5(PNPT1):c.-158G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 697,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PNPT1
NM_033109.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.814

Publications

0 publications found

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 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

PNPT1 links:

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ACMG classification

Classification was made for transcript

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 (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
PNPT1	NM_033109.5 link	c.-158G>T	upstream_gene_variant	ENST00000447944.7	NP_149100.2	Q8TCS8
PNPT1	XM_005264629.3 link	c.-394G>T	upstream_gene_variant		XP_005264686.1
PNPT1	XM_017005172.2 link	c.-337G>T	upstream_gene_variant		XP_016860661.1
PNPT1	XM_047446161.1 link	c.-158G>T	upstream_gene_variant		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7 link	c.-158G>T		upstream_gene_variant		1	NM_033109.5	ENSP00000400646.2		Q8TCS8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

697166

Hom.:

AF XY:

0.00000282

AC XY:

AN XY:

353996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17662

American (AMR)

AF:

0.00

AC:

AN:

19618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15274

East Asian (EAS)

AF:

0.00

AC:

AN:

32128

South Asian (SAS)

AF:

0.00

AC:

AN:

51416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2482

European-Non Finnish (NFE)

AF:

0.00000202

AC:

AN:

494264

Other (OTH)

AF:

0.00

AC:

AN:

34204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.3

(source)

DANN

Benign

0.80

PhyloP100

-0.81

PromoterAI

-0.097

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over