chr2-55659467-T-C

Variant names:

• chr2-55659467-T-C
• rs782606
• NM_033109.5:c.1284+690A>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.1284+690A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 151,628 control chromosomes in the GnomAD database, including 16,170 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 (16170 hom., cov: 30)
• Consequence: PNPT1 NM_033109.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.712
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPT1	NM_033109.5	c.1284+690A>G		intron_variant	Intron 15 of 27	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3	c.1044+690A>G		intron_variant	Intron 15 of 27		XP_005264686.1
PNPT1	XM_017005172.2	c.1044+690A>G		intron_variant	Intron 14 of 26		XP_016860661.1
PNPT1	XM_047446161.1	c.1284+690A>G		intron_variant	Intron 15 of 19		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7	c.1284+690A>G		intron_variant	Intron 15 of 27	1	NM_033109.5	ENSP00000400646.2
PNPT1	ENST00000260604.8	n.*839+690A>G		intron_variant	Intron 14 of 26	5		ENSP00000260604.4
PNPT1	ENST00000415374.5	n.1284+690A>G		intron_variant	Intron 15 of 28	5		ENSP00000393953.1
PNPT1	ENST00000415489.1	n.357+690A>G		intron_variant	Intron 5 of 7	3		ENSP00000411057.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67784 AN: 151512 Hom.: 16175 Cov.: 30

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.474

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

GnomAD4 genome AF: 0.447 AC: 67797 AN: 151628 Hom.: 16170 Cov.: 30 AF XY: 0.445 AC XY: 32952 AN XY: 74046

African (AFR) AF: 0.326 AC: 13466 AN: 41344

American (AMR) AF: 0.495 AC: 7524 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1674 AN: 3458

East Asian (EAS) AF: 0.105 AC: 542 AN: 5162

South Asian (SAS) AF: 0.261 AC: 1256 AN: 4810

European-Finnish (FIN) AF: 0.588 AC: 6148 AN: 10454

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35782 AN: 67884

Other (OTH) AF: 0.471 AC: 988 AN: 2096

Alfa AF: 0.500 Hom.: 31559

Bravo AF: 0.435

Asia WGS AF: 0.233 AC: 810 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.35
PhyloP100		-0.71
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: rs782606; hg19: chr2-55886602;