Genetic Variant PUS1:p.Arg295Trp (chr12-131941630-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_025215.6(PUS1):c.883C>T(p.Arg295Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,052 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PUS1
NM_025215.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.828

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 12-131941630-C-T is Pathogenic according to our data. Variant chr12-131941630-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 221982.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUS1	NM_025215.6 link	c.883C>T	p.Arg295Trp	missense_variant	Exon 5 of 6	ENST00000376649.8	NP_079491.2	Q9Y606-1E5KMT5
PUS1	NM_001002019.3 link	c.799C>T	p.Arg267Trp	missense_variant	Exon 5 of 6		NP_001002019.1	Q9Y606-2E5KMT6
PUS1	NM_001002020.3 link	c.799C>T	p.Arg267Trp	missense_variant	Exon 5 of 6		NP_001002020.1	Q9Y606-2E5KMT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUS1	ENST00000376649.8 link	c.883C>T	p.Arg295Trp	missense_variant	Exon 5 of 6	1	NM_025215.6	ENSP00000365837.3		Q9Y606-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

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

Bravo

AF:

0.0000227

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 1

Pathogenic:2

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

.;T;.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;H;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.6

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.99

MutPred

0.74

.;Gain of ubiquitination at K296 (P = 0.0573);.;.;

MVP

1.0

MPC

1.0

ClinPred

0.99

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.98

gMVP

0.97

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