Variant chr11-125893928-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_031307.4(PUS3):c.1303C>T(p.Arg435Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,886 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PUS3
NM_031307.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0989 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-125893928-G-A is Pathogenic according to our data. Variant chr11-125893928-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 253169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-125893928-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUS3	NM_031307.4 linkuse as main transcript	c.1303C>T	p.Arg435Ter	stop_gained	4/4	ENST00000227474.8	NP_112597.4
HYLS1	NM_001134793.2 linkuse as main transcript	c.-26+2456G>A		intron_variant		ENST00000425380.7	NP_001128265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUS3	ENST00000227474.8 linkuse as main transcript	c.1303C>T	p.Arg435Ter	stop_gained	4/4	1	NM_031307.4	ENSP00000227474	P1
HYLS1	ENST00000425380.7 linkuse as main transcript	c.-26+2456G>A		intron_variant		3	NM_001134793.2	ENSP00000414884	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000212

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000261

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2021	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 24, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

D;D;D;D;D

Vest4

0.34

GERP RS

1.7

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.

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