chr1-1309527-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_153339.3(PUSL1):​c.397C>T​(p.Arg133Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,280 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PUSL1
NM_153339.3 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.51
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PUSL1NM_153339.3 linkc.397C>T p.Arg133Cys missense_variant Exon 4 of 8 ENST00000379031.10 NP_699170.1 Q8N0Z8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PUSL1ENST00000379031.10 linkc.397C>T p.Arg133Cys missense_variant Exon 4 of 8 1 NM_153339.3 ENSP00000368318.5 Q8N0Z8-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000117
AC:
17
AN:
1459066
Hom.:
0
Cov.:
33
AF XY:
0.0000110
AC XY:
8
AN XY:
725744
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000202
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000193
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000724
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.397C>T (p.R133C) alteration is located in exon 4 (coding exon 4) of the PUSL1 gene. This alteration results from a C to T substitution at nucleotide position 397, causing the arginine (R) at amino acid position 133 to be replaced by a cysteine (C). 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
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Uncertain
0.46
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.79
MutPred
0.55
Gain of catalytic residue at L134 (P = 0.0101);
MVP
0.59
MPC
0.52
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.83
gMVP
0.82

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.

Other links and lift over

dbSNP: rs903376939; hg19: chr1-1244907; API