2-55640638-C-G

Variant names:

• chr2-55640638-C-G
• rs752550279
• NM_033109.5:c.2137G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_033109.5(PNPT1):​c.2137G>C​(p.Asp713His) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,433,644 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D713Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.45
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-55640638-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 587377.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2137G>C	p.Asp713His	missense	Exon 26 of 28	NP_149100.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPT1	ENST00000447944.7	TSL:1 MANE Select	c.2137G>C	p.Asp713His	missense	Exon 26 of 28	ENSP00000400646.2
	PNPT1	ENST00000260604.8	TSL:5	n.*1679G>C		non_coding_transcript_exon	Exon 25 of 27	ENSP00000260604.4
	PNPT1	ENST00000415374.5	TSL:5	n.2137G>C		non_coding_transcript_exon	Exon 26 of 29	ENSP00000393953.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433644 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 714770

African (AFR) AF: 0.00 AC: 0 AN: 32798

American (AMR) AF: 0.00 AC: 0 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 85518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5198

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087460

Other (OTH) AF: 0.0000168 AC: 1 AN: 59482

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.40		Loss of ubiquitination at K718 (P = 0.0382)
MVP		0.50
MPC		0.67
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.64
Mutation Taster		=31/69	disease causing

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: rs752550279; hg19: chr2-55867773;