2-55693981-C-G

Variant names:

• chr2-55693981-C-G
• rs782584
• NM_033109.5:c.-158G>C

Variant summary

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

The NM_033109.5(PNPT1):​c.-158G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 847,598 control chromosomes in the GnomAD database, including 92,453 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 0.44 (15474 hom., cov: 33)
  • Exomes 𝑓: 0.46 (76979 hom.)
• Consequence: PNPT1 NM_033109.5 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.814
• Publications: 10 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66597 AN: 151988 Hom.: 15477 Cov.: 33

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.462

GnomAD4 exome AF: 0.458 AC: 318835 AN: 695492 Hom.: 76979 AF XY: 0.452 AC XY: 159614 AN XY: 353202

African (AFR) AF: 0.325 AC: 5728 AN: 17602

American (AMR) AF: 0.468 AC: 9168 AN: 19592

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 7303 AN: 15248

East Asian (EAS) AF: 0.121 AC: 3880 AN: 32114

South Asian (SAS) AF: 0.269 AC: 13833 AN: 51374

European-Finnish (FIN) AF: 0.556 AC: 16737 AN: 30094

Middle Eastern (MID) AF: 0.415 AC: 1030 AN: 2480

European-Non Finnish (NFE) AF: 0.499 AC: 245737 AN: 492840

Other (OTH) AF: 0.452 AC: 15419 AN: 34148

GnomAD4 genome AF: 0.438 AC: 66615 AN: 152106 Hom.: 15474 Cov.: 33 AF XY: 0.436 AC XY: 32414 AN XY: 74372

African (AFR) AF: 0.334 AC: 13869 AN: 41472

American (AMR) AF: 0.489 AC: 7467 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3468

East Asian (EAS) AF: 0.110 AC: 568 AN: 5176

South Asian (SAS) AF: 0.258 AC: 1245 AN: 4824

European-Finnish (FIN) AF: 0.566 AC: 5987 AN: 10586

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34444 AN: 67990

Other (OTH) AF: 0.459 AC: 970 AN: 2112

Alfa AF: 0.474 Hom.: 2144

Bravo AF: 0.428

Asia WGS AF: 0.231 AC: 805 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.6
DANN	Benign	0.67
PhyloP100		-0.81
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs782584; hg19: chr2-55921116;