Genetic Variant PUSL1:p.Arg36Ser (chr1-1308943-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_153339.3(PUSL1):c.106C>A(p.Arg36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,420,258 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 2 hom. )

Consequence

PUSL1
NM_153339.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.214

Publications

2 publications found

Variant links:

Genes affected

PUSL1 (HGNC:26914): (pseudouridine synthase like 1) Predicted to enable pseudouridine synthase activity. Predicted to be involved in tRNA pseudouridine synthesis. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

PUSL1 links:

ACAP3 (HGNC:16754): (ArfGAP with coiled-coil, ankyrin repeat and PH domains 3) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within neuron migration and regulation of neuron projection development. Predicted to be located in growth cone. [provided by Alliance of Genome Resources, Apr 2022]

ACAP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009332687).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153339.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PUSL1	NM_153339.3	MANE Select	c.106C>A	p.Arg36Ser	missense	Exon 2 of 8	NP_699170.1	Q8N0Z8-1
PUSL1	NM_001346116.2		c.106C>A	p.Arg36Ser	missense	Exon 2 of 8	NP_001333045.1
PUSL1	NR_144369.2		n.125-143C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PUSL1	ENST00000379031.10	TSL:1 MANE Select	c.106C>A	p.Arg36Ser	missense	Exon 2 of 8	ENSP00000368318.5	Q8N0Z8-1
PUSL1	ENST00000892133.1		c.106C>A	p.Arg36Ser	missense	Exon 2 of 8	ENSP00000562192.1
PUSL1	ENST00000892132.1		c.85C>A	p.Arg29Ser	missense	Exon 2 of 8	ENSP00000562191.1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000656

AC:

AN:

56430

AF XY:

0.000729

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000703

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000347

Gnomad NFE exome

AF:

0.000941

Gnomad OTH exome

AF:

0.00107

GnomAD4 exome

AF:

0.000953

AC:

1208

AN:

1268044

Hom.:

Cov.:

AF XY:

0.000864

AC XY:

533

AN XY:

616700

show subpopulations

African (AFR)

AF:

0.0000796

AC:

AN:

25134

American (AMR)

AF:

0.000480

AC:

AN:

16658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17816

East Asian (EAS)

AF:

0.00

AC:

AN:

29828

South Asian (SAS)

AF:

0.000391

AC:

AN:

58852

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

41782

Middle Eastern (MID)

AF:

0.00195

AC:

AN:

3586

European-Non Finnish (NFE)

AF:

0.00110

AC:

1121

AN:

1022626

Other (OTH)

AF:

0.000773

AC:

AN:

51762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

142

214

285

356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000519

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41542

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000956

AC:

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000864

Hom.:

Bravo

AF:

0.000574

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000766

AC:

ExAC

AF:

0.000582

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0069

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.0093

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.27

PhyloP100

0.21

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.46

REVEL

Benign

0.16

Sift

Benign

0.74

Sift4G

Benign

0.82

Polyphen

0.023

Vest4

0.24

MVP

0.31

MPC

0.093

ClinPred

0.027

GERP RS

4.5

PromoterAI

0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.17

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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