NM_025215.6:c.-182C>T

Variant names:

• chr12-131929541-C-T
• rs61942438
• NM_025215.6:c.-182C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025215.6(PUS1):​c.-182C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 528,408 control chromosomes in the GnomAD database, including 3,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1600 hom., cov: 30)
  • Exomes 𝑓: 0.080 (1623 hom.)
• Consequence: PUS1 NM_025215.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.59

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]

PUS1-AS1 (HGNC:40706): (PUS1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-131929541-C-T is Benign according to our data. Variant chr12-131929541-C-T is described in ClinVar as [Benign]. Clinvar id is 307697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-131929541-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUS1	NM_025215.6	c.-182C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	ENST00000376649.8	NP_079491.2
PUS1	NM_025215.6	c.-182C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000376649.8	NP_079491.2
PUS1	NM_001002019.3	c.-11+137C>T		intron_variant	Intron 1 of 5		NP_001002019.1
PUS1	NM_001002020.3	c.-11+161C>T		intron_variant	Intron 1 of 5		NP_001002020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUS1	ENST00000376649	c.-182C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	1	NM_025215.6	ENSP00000365837.3
PUS1	ENST00000376649	c.-182C>T		5_prime_UTR_variant	Exon 1 of 6	1	NM_025215.6	ENSP00000365837.3

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18464 AN: 151338 Hom.: 1600 Cov.: 30

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0780

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0685

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0616

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0797 AC: 30038 AN: 376952 Hom.: 1623 Cov.: 5 AF XY: 0.0800 AC XY: 15953 AN XY: 199424

Gnomad4 AFR exome AF: 0.232

Gnomad4 AMR exome AF: 0.0781

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0922

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.0578

Gnomad4 OTH exome AF: 0.0884

GnomAD4 genome AF: 0.122 AC: 18492 AN: 151456 Hom.: 1600 Cov.: 30 AF XY: 0.127 AC XY: 9370 AN XY: 73972

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.0778

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0683

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.0616

Gnomad4 OTH AF: 0.105

Alfa AF: 0.0510 Hom.: 72

Bravo AF: 0.117

Asia WGS AF: 0.0950 AC: 330 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Myopathy, lactic acidosis, and sideroblastic anemia 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.4
DANN	Benign	0.87
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3

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

LitVar

Other links and lift over

dbSNP: rs61942438; hg19: chr12-132414086;