2-55665126-A-C

Variant names:

• chr2-55665126-A-C
• rs2586954
• NM_033109.5:c.1176+1865T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033109.5(PNPT1):​c.1176+1865T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 151,934 control chromosomes in the GnomAD database, including 16,320 homozygotes. 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: 𝑓 0.45 (16320 hom., cov: 32)
• Consequence: PNPT1 NM_033109.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.306
• Publications: 11 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	NM_033109.5	MANE Select	c.1176+1865T>G		intron	N/A	NP_149100.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.1176+1865T>G		intron	N/A	ENSP00000400646.2
	PNPT1	ENST00000260604.8	TSL:5	n.*731+1865T>G		intron	N/A	ENSP00000260604.4
	PNPT1	ENST00000415374.5	TSL:5	n.1176+1865T>G		intron	N/A	ENSP00000393953.1

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68292 AN: 151818 Hom.: 16325 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.476

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.450 AC: 68302 AN: 151934 Hom.: 16320 Cov.: 32 AF XY: 0.448 AC XY: 33255 AN XY: 74260

African (AFR) AF: 0.321 AC: 13317 AN: 41434

American (AMR) AF: 0.497 AC: 7574 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1695 AN: 3472

East Asian (EAS) AF: 0.160 AC: 831 AN: 5180

South Asian (SAS) AF: 0.261 AC: 1260 AN: 4822

European-Finnish (FIN) AF: 0.590 AC: 6200 AN: 10502

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.530 AC: 35998 AN: 67964

Other (OTH) AF: 0.473 AC: 998 AN: 2110

Alfa AF: 0.470 Hom.: 10736

Bravo AF: 0.438

Asia WGS AF: 0.251 AC: 871 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.83
DANN	Benign	0.44
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs2586954; hg19: chr2-55892261;