2-55635640-C-T

Variant names:

• chr2-55635640-C-T
• rs782652
• NM_033109.5:c.*597G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_033109.5(PNPT1):​c.*597G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 151,284 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: 𝑓 0.00017 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: PNPT1 NM_033109.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.639
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000172 (26/151284) while in subpopulation EAS AF = 0.00468 (24/5128). AF 95% confidence interval is 0.00323. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	NM_033109.5	MANE Select	c.*597G>A		3_prime_UTR	Exon 28 of 28	NP_149100.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.*597G>A		3_prime_UTR	Exon 28 of 28	ENSP00000400646.2
	PNPT1	ENST00000917023.1		c.*597G>A		3_prime_UTR	Exon 28 of 28	ENSP00000587082.1
	PNPT1	ENST00000949801.1		c.*597G>A		3_prime_UTR	Exon 28 of 28	ENSP00000619860.1

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00447

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.000172 AC: 26 AN: 151284 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 13 AN XY: 73868

African (AFR) AF: 0.0000242 AC: 1 AN: 41274

American (AMR) AF: 0.00 AC: 0 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00468 AC: 24 AN: 5128

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67856

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.00 Hom.: 4708

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.8
DANN	Benign	0.72
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

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: rs782652; hg19: chr2-55862775;