chr12-131929270-C-T

Variant names:

• chr12-131929270-C-T
• rs551126678
• ENST00000443358.6:c.-121C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000443358.6(PUS1):​c.-121C>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 0.00153 in 168,496 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: PUS1 ENST00000443358.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0180
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00165 (252/152274) while in subpopulation AFR AF = 0.00513 (213/41542). AF 95% confidence interval is 0.00456. There are 2 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000443358.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS1	NM_025215.6	MANE Select	c.-453C>T		upstream_gene	N/A	NP_079491.2	E5KMT5
	PUS1	NM_001002019.3		c.-145C>T		upstream_gene	N/A	NP_001002019.1	E5KMT6
	PUS1	NM_001002020.3		c.-121C>T		upstream_gene	N/A	NP_001002020.1	E5KMT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS1	ENST00000443358.6	TSL:1	c.-121C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000392451.2	Q9Y606-2
	PUS1	ENST00000443358.6	TSL:1	c.-121C>T		5_prime_UTR	Exon 1 of 6	ENSP00000392451.2	Q9Y606-2
	PUS1	ENST00000322060.9	TSL:5	c.-26C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000324726.5	G8JLB3

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152158 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.000370 AC: 6 AN: 16222 Hom.: 0 Cov.: 0 AF XY: 0.000241 AC XY: 2 AN XY: 8310

African (AFR) AF: 0.00481 AC: 3 AN: 624

American (AMR) AF: 0.00244 AC: 1 AN: 410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 706

East Asian (EAS) AF: 0.00 AC: 0 AN: 920

South Asian (SAS) AF: 0.00 AC: 0 AN: 362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.0000885 AC: 1 AN: 11302

Other (OTH) AF: 0.000917 AC: 1 AN: 1090

GnomAD4 genome AF: 0.00165 AC: 252 AN: 152274 Hom.: 2 Cov.: 30 AF XY: 0.00185 AC XY: 138 AN XY: 74442

African (AFR) AF: 0.00513 AC: 213 AN: 41542

American (AMR) AF: 0.00170 AC: 26 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.00181

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Myopathy, lactic acidosis, and sideroblastic anemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	10
DANN	Benign	0.96
PhyloP100		-0.018
PromoterAI		-0.099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs551126678; hg19: chr12-132413815;