rs374698153

Variant names:

• chr2-55647357-G-A
• rs374698153
• NM_033109.5:c.1592C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-55647357-G-A
• chr2-55647357-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_033109.5(PNPT1):​c.1592C>T​(p.Thr531Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. T531R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PNPT1 NM_033109.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-55647357-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209184.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPT1	NM_033109.5	c.1592C>T	p.Thr531Ile	missense_variant	Exon 19 of 28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3	c.1352C>T	p.Thr451Ile	missense_variant	Exon 19 of 28		XP_005264686.1
PNPT1	XM_017005172.2	c.1352C>T	p.Thr451Ile	missense_variant	Exon 18 of 27		XP_016860661.1
PNPT1	XM_047446161.1	c.*124C>T		3_prime_UTR_variant	Exon 20 of 20		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7	c.1592C>T	p.Thr531Ile	missense_variant	Exon 19 of 28	1	NM_033109.5	ENSP00000400646.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452974 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722620

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 44030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 84240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107258

Other (OTH) AF: 0.00 AC: 0 AN: 59916

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.65		Loss of phosphorylation at T531 (P = 0.0827);
MVP		0.66
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.91
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374698153; hg19: chr2-55874492;