NM_031307.4:c.1409G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031307.4(PUS3):c.1409G>A(p.Arg470Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PUS3
NM_031307.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.612

Publications

0 publications found

Variant links:

Genes affected

PUS3 (HGNC:25461): (pseudouridine synthase 3) The protein encoded by this gene catalyzes the formation of tRNA pseudouridine from tRNA uridine at position 39 in the anticodon stem and loop of transfer RNAs. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

PUS3 links:

HYLS1 (HGNC:26558): (HYLS1 centriolar and ciliogenesis associated) This gene encodes a protein localized to the cytoplasm. Mutations in this gene are associated with hydrolethalus syndrome. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Oct 2008]

HYLS1 Gene-Disease associations (from GenCC):

hydrolethalus syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
hydrolethalus syndrome
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HYLS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06158662).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031307.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PUS3	NM_031307.4	MANE Select	c.1409G>A	p.Arg470Lys	missense	Exon 4 of 4	NP_112597.4
HYLS1	NM_001134793.2	MANE Select	c.-26+2350C>T		intron	N/A	NP_001128265.1	Q96M11
PUS3	NM_001441237.1		c.1409G>A	p.Arg470Lys	missense	Exon 5 of 5	NP_001428166.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PUS3	ENST00000227474.8	TSL:1 MANE Select	c.1409G>A	p.Arg470Lys	missense	Exon 4 of 4	ENSP00000227474.3	Q9BZE2
PUS3	ENST00000530811.5	TSL:1	c.1409G>A	p.Arg470Lys	missense	Exon 3 of 3	ENSP00000432386.1	Q9BZE2
HYLS1	ENST00000425380.7	TSL:3 MANE Select	c.-26+2350C>T		intron	N/A	ENSP00000414884.2	Q96M11

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152052

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251220

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111882

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41502

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000912

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.2

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0061

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.54

M_CAP

Benign

0.0051

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

PhyloP100

0.61

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.37

REVEL

Benign

0.021

Sift

Benign

0.23

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.12

MVP

0.36

MPC

0.095

ClinPred

0.021

GERP RS

-0.81

Varity_R

0.027

gMVP

0.42

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over