rs752550279

Positions:

• chr2-55640638-C-A
• chr2-55640638-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000447944.7(PNPT1):​c.2137G>T​(p.Asp713Tyr) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNPT1 ENST00000447944.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.45

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• PP5: Variant 2-55640638-C-A is Pathogenic according to our data. Variant chr2-55640638-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 587377.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-55640638-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPT1	NM_033109.5	c.2137G>T	p.Asp713Tyr	missense_variant	26/28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3	c.1897G>T	p.Asp633Tyr	missense_variant	26/28		XP_005264686.1
PNPT1	XM_017005172.2	c.1897G>T	p.Asp633Tyr	missense_variant	25/27		XP_016860661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7	c.2137G>T	p.Asp713Tyr	missense_variant	26/28	1	NM_033109.5	ENSP00000400646	P1
PNPT1	ENST00000481066.1	n.1199G>T		non_coding_transcript_exon_variant	7/9	5
PNPT1	ENST00000415374.5	c.2137G>T	p.Asp713Tyr	missense_variant, NMD_transcript_variant	26/29	5		ENSP00000393953
PNPT1	ENST00000260604.8	c.*1679G>T		3_prime_UTR_variant, NMD_transcript_variant	25/27	5		ENSP00000260604

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433642 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 714770

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined oxidative phosphorylation defect type 13 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.44		Loss of ubiquitination at K718 (P = 0.0362);
MVP		0.51
MPC		0.69
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752550279; hg19: chr2-55867773;