chr12-131929541-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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 -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 VariationId is 307697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025215.6. 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.-182C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_079491.2	E5KMT5
	PUS1	NM_025215.6	MANE Select	c.-182C>T		5_prime_UTR	Exon 1 of 6	NP_079491.2	E5KMT5
	PUS1	NM_001002019.3		c.-11+137C>T		intron	N/A	NP_001002019.1	E5KMT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS1	ENST00000376649.8	TSL:1 MANE Select	c.-182C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000365837.3	Q9Y606-1
	PUS1	ENST00000376649.8	TSL:1 MANE Select	c.-182C>T		5_prime_UTR	Exon 1 of 6	ENSP00000365837.3	Q9Y606-1
	PUS1	ENST00000443358.6	TSL:1	c.-11+161C>T		intron	N/A	ENSP00000392451.2	Q9Y606-2

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

African (AFR) AF: 0.232 AC: 1899 AN: 8176

American (AMR) AF: 0.0781 AC: 866 AN: 11086

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 1228 AN: 11252

East Asian (EAS) AF: 0.0922 AC: 2199 AN: 23850

South Asian (SAS) AF: 0.105 AC: 3489 AN: 33138

European-Finnish (FIN) AF: 0.164 AC: 4449 AN: 27074

Middle Eastern (MID) AF: 0.0874 AC: 152 AN: 1740

European-Non Finnish (NFE) AF: 0.0578 AC: 13787 AN: 238364

Other (OTH) AF: 0.0884 AC: 1969 AN: 22272

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

African (AFR) AF: 0.230 AC: 9496 AN: 41232

American (AMR) AF: 0.0778 AC: 1185 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 422 AN: 3466

East Asian (EAS) AF: 0.0683 AC: 351 AN: 5140

South Asian (SAS) AF: 0.104 AC: 495 AN: 4750

European-Finnish (FIN) AF: 0.200 AC: 2098 AN: 10498

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0616 AC: 4180 AN: 67844

Other (OTH) AF: 0.105 AC: 221 AN: 2098

Alfa AF: 0.0632 Hom.: 164

Bravo AF: 0.117

Asia WGS AF: 0.0950 AC: 330 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Myopathy, lactic acidosis, and sideroblastic anemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.4
DANN	Benign	0.87
PhyloP100		-3.6
PromoterAI		-0.059	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61942438; hg19: chr12-132414086;