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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144709.4(PUS10):c.1482C>A(p.Phe494Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PUS10
NM_144709.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.535

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144709.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PUS10	NM_144709.4	MANE Select	c.1482C>A	p.Phe494Leu	missense	Exon 17 of 18	NP_653310.2	Q3MIT2
PUS10	NM_001322123.1		c.1482C>A	p.Phe494Leu	missense	Exon 17 of 18	NP_001309052.1	Q3MIT2
PUS10	NM_001322124.1		c.1482C>A	p.Phe494Leu	missense	Exon 17 of 18	NP_001309053.1	A8K6R4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PUS10	ENST00000316752.11	TSL:1 MANE Select	c.1482C>A	p.Phe494Leu	missense	Exon 17 of 18	ENSP00000326003.6	Q3MIT2
PUS10	ENST00000602599.1	TSL:1	n.4085C>A		non_coding_transcript_exon	Exon 15 of 16
PUS10	ENST00000971235.1		c.1506C>A	p.Phe502Leu	missense	Exon 18 of 19	ENSP00000641294.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461572

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111746

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.1

PhyloP100

0.54

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.35

Sift

Benign

0.32

Sift4G

Benign

0.30

Polyphen

1.0

Vest4

0.90

MutPred

0.36

Gain of disorder (P = 0.139)

MVP

0.25

MPC

0.25

ClinPred

0.95

GERP RS

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.62

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.47

Position offset: 30

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over