12-131929732-C-T

Position:

• chr12-131929732-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_025215.6(PUS1):​c.10C>T​(p.Gln4Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PUS1 NM_025215.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0800

Genes affected

PUS1 (HGNC:15508): (pseudouridine synthase 1) This gene encodes a pseudouridine synthase that converts uridine to pseudouridine once it has been incorporated into an RNA molecule. The encoded enzyme may play an essential role in tRNA function and in stabilizing the secondary and tertiary structure of many RNAs. A mutation in this gene has been linked to mitochondrial myopathy and sideroblastic anemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.992 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 12-131929732-C-T is Pathogenic according to our data. Variant chr12-131929732-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1361128.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUS1	NM_025215.6	c.10C>T	p.Gln4Ter	stop_gained	1/6	ENST00000376649.8	NP_079491.2
PUS1	NM_001002019.3	c.-10-175C>T		intron_variant			NP_001002019.1
PUS1	NM_001002020.3	c.-10-175C>T		intron_variant			NP_001002020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUS1	ENST00000376649.8	c.10C>T	p.Gln4Ter	stop_gained	1/6	1	NM_025215.6	ENSP00000365837

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1439204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 716132

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PUS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln4*) in the PUS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PUS1 are known to be pathogenic (PMID: 17056637, 19731322, 25058219, 26556812). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.031
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.13	N
MutationTaster	Benign	1.0	A;N;N;N
Vest4		0.24
GERP RS		0.47
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-132414277;