2-55636166-A-G

Variant names:

• chr2-55636166-A-G
• rs72930820
• NM_033109.5:c.*71T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033109.5(PNPT1):​c.*71T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,108,716 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (149 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (91 hom.)
• Consequence: PNPT1 NM_033109.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.560
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-55636166-A-G is Benign according to our data. Variant chr2-55636166-A-G is described in ClinVar as Benign. ClinVar VariationId is 1261362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	NM_033109.5	MANE Select	c.*71T>C		3_prime_UTR	Exon 28 of 28	NP_149100.2	Q8TCS8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.*71T>C		3_prime_UTR	Exon 28 of 28	ENSP00000400646.2	Q8TCS8
	PNPT1	ENST00000917025.1		c.*71T>C		3_prime_UTR	Exon 28 of 28	ENSP00000587084.1
	PNPT1	ENST00000867135.1		c.*71T>C		3_prime_UTR	Exon 28 of 28	ENSP00000537194.1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3629 AN: 152114 Hom.: 149 Cov.: 33

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0201

GnomAD4 exome AF: 0.00253 AC: 2419 AN: 956484 Hom.: 91 Cov.: 12 AF XY: 0.00217 AC XY: 1046 AN XY: 481068

African (AFR) AF: 0.0843 AC: 1889 AN: 22404

American (AMR) AF: 0.00610 AC: 143 AN: 23446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18752

East Asian (EAS) AF: 0.00 AC: 0 AN: 35182

South Asian (SAS) AF: 0.000201 AC: 11 AN: 54846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39334

Middle Eastern (MID) AF: 0.00462 AC: 14 AN: 3032

European-Non Finnish (NFE) AF: 0.000142 AC: 102 AN: 717098

Other (OTH) AF: 0.00613 AC: 260 AN: 42390

GnomAD4 genome AF: 0.0239 AC: 3634 AN: 152232 Hom.: 149 Cov.: 33 AF XY: 0.0229 AC XY: 1708 AN XY: 74466

African (AFR) AF: 0.0824 AC: 3422 AN: 41520

American (AMR) AF: 0.0101 AC: 155 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68020

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0126 Hom.: 30

Bravo AF: 0.0274

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.47
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs72930820; hg19: chr2-55863301;