12-131932301-C-T

Position:

chr12-131932301-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000376649.8(PUS1):c.430C>T(p.Arg144Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,376 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PUS1
ENST00000376649.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.82

Variant links:

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]

PUS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 12-131932301-C-T is Pathogenic according to our data. Variant chr12-131932301-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PUS1	NM_025215.6 linkuse as main transcript	c.430C>T	p.Arg144Trp	missense_variant	3/6	ENST00000376649.8	NP_079491.2
PUS1	NM_001002019.3 linkuse as main transcript	c.346C>T	p.Arg116Trp	missense_variant	3/6		NP_001002019.1
PUS1	NM_001002020.3 linkuse as main transcript	c.346C>T	p.Arg116Trp	missense_variant	3/6		NP_001002020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUS1	ENST00000376649.8 linkuse as main transcript	c.430C>T	p.Arg144Trp	missense_variant	3/6	1	NM_025215.6	ENSP00000365837		Q9Y606-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251058

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461162

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.430C>T (p.Arg144Trp) variant in PUS1 gene has been reported previously in individuals affected with PUS1-related disorders (Bykhovskaya et al., 2004). It has also been observed to segregate with disease in related individuals. Patient derived cell lines and in vitro functional assays suggest this substitution results in a loss of pseudouridine synthase activity (Patton et al., 2005; Sibert et al., 2008). The p.Arg144Trp variant is present with allele frequency of 0.0008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg144Trp in PUS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 144 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2022	Variant summary: PUS1 c.430C>T (p.Arg144Trp) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved amino acid within the catalytic center of the protein (Bykhovskaya_2004). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 252926 control chromosomes. c.430C>T has been reported in the literature in multiple individuals affected with Mitochondrial myopathy and sideroblastic anaemia, with evidence of cosegregation (Bykhovskaya_2004, Zeharia_2005). These data indicate that the variant is very likely to be associated with disease. Patient derived cell lines and in vitro functional assays suggest this substitution results in a loss of pseudouridine synthase activity (Patton_2005, Sibert_2008). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 144 of the PUS1 protein (p.Arg144Trp). This variant is present in population databases (rs104894371, gnomAD 0.007%). This missense change has been observed in individuals with mitochondrial myopathy and sideroblastic anemia (MLASA) (PMID: 15108122, 15971356). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2536). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PUS1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

.;D;.;D;D;.;D;.;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

4.7

.;H;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.9

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;.;D;.;.;.;.;.

Vest4

0.99

MVP

0.90

MPC

1.0

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.91

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over