12-131941464-C-A

Position:

• chr12-131941464-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025215.6(PUS1):​c.717C>A​(p.Tyr239Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PUS1 NM_025215.6 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.16

Genes affected

PUS1 (HGNC:15508): (pseudouridine synthase 1) This gene encodes a pseudouridine synthase that converts uridine to pseudouridine once it has been incorporated into an RNA molecule. The encoded enzyme may play an essential role in tRNA function and in stabilizing the secondary and tertiary structure of many RNAs. A mutation in this gene has been linked to mitochondrial myopathy and sideroblastic anemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-131941464-C-A is Pathogenic according to our data. Variant chr12-131941464-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUS1	NM_025215.6	c.717C>A	p.Tyr239Ter	stop_gained	5/6	ENST00000376649.8	NP_079491.2
PUS1	NM_001002019.3	c.633C>A	p.Tyr211Ter	stop_gained	5/6		NP_001002019.1
PUS1	NM_001002020.3	c.633C>A	p.Tyr211Ter	stop_gained	5/6		NP_001002020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUS1	ENST00000376649.8	c.717C>A	p.Tyr239Ter	stop_gained	5/6	1	NM_025215.6	ENSP00000365837

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	The c.633C>A (p.Tyr211ter) novel nonsense variant in the PUS1 gene is predicted to cause a premature protein truncation that lacks 188 amino acids (NP_001002020) in the C-terminal region of the protein. The C-terminal portion, which is predicted to be deleted as a result of this variant, comprises three helices that are necessary to maintain structural integrity and stability (Czudnochowski N et al., 2013). Indeed, a mutant form of hPus1 that lacks the important three helical domains in the C-terminal end was unable to solubilize (Czudnochowski N et al., 2013). Furthermore, Fernandez-Vizarra E et al. (2007) reported that two brothers who were affected with MLASA carried a homozygous variant (p.Glu192ter) that was also predicted to ablate the three C-terminal helices of the protein. This locus is conserved across species. The frequency of this variant is either absent or very low in the population databases (1000 Genome, Exome Sequencing Project and ExAC) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 15, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;A;A;D
Vest4		0.80
GERP RS		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs779651314; hg19: chr12-132426009;