Genetic Variant PUS10:p.Phe494Leu (chr2-60945078-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144709.4(PUS10):c.1482C>G(p.Phe494Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PUS10
NM_144709.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.535

Variant links:

Genes affected

PUS10 (HGNC:26505): (pseudouridine synthase 10) Pseudouridination, the isomerization of uridine to pseudouridine, is the most common posttranscriptional nucleotide modification found in RNA and is essential for biologic functions such as spliceosome biogenesis. Pseudouridylate synthases, such as PUS10, catalyze pseudouridination of structural RNAs, including transfer, ribosomal, and splicing RNAs. These enzymes also act as RNA chaperones, facilitating the correct folding and assembly of tRNAs (McCleverty et al., 2007 [PubMed 17900615]).[supplied by OMIM, May 2009]

PUS10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUS10	NM_144709.4 link	c.1482C>G	p.Phe494Leu	missense_variant	Exon 17 of 18	ENST00000316752.11	NP_653310.2	Q3MIT2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PUS10	ENST00000316752.11 link	c.1482C>G	p.Phe494Leu	missense_variant	Exon 17 of 18	1	NM_144709.4	ENSP00000326003.6	Q3MIT2
PUS10	ENST00000602599.1 link	n.4085C>G		non_coding_transcript_exon_variant	Exon 15 of 16	1
PUS10	ENST00000407787.5 link	c.1482C>G	p.Phe494Leu	missense_variant	Exon 17 of 18	2		ENSP00000386074.1	Q3MIT2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152162

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251440

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1461570

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1482C>G (p.F494L) alteration is located in exon 17 (coding exon 16) of the PUS10 gene. This alteration results from a C to G substitution at nucleotide position 1482, causing the phenylalanine (F) at amino acid position 494 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.96

.;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.1

L;L

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.32

T;T

Sift4G

Benign

0.30

T;T

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.36

Gain of disorder (P = 0.139);Gain of disorder (P = 0.139);

MVP

0.25

MPC

0.25

ClinPred

0.76

GERP RS

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: 30

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