ENST00000539078.2:n.458A>C

Variant names:

• chr12-131929189-T-G
• rs559360646
• ENST00000539078.2:n.458A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000539078.2(PUS1-AS1):​n.458A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 148,414 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PUS1-AS1 ENST00000539078.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.453
• Publications: 0 publications found

Genes affected

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

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopathy, lactic acidosis, and sideroblastic anemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• myopathy, lactic acidosis, and sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.19).
• BP6: Variant 12-131929189-T-G is Benign according to our data. Variant chr12-131929189-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 678339.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000539078.2. 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.-534T>G		upstream_gene	N/A	NP_079491.2	E5KMT5
	PUS1	NM_001002019.3		c.-226T>G		upstream_gene	N/A	NP_001002019.1	E5KMT6
	PUS1	NM_001002020.3		c.-202T>G		upstream_gene	N/A	NP_001002020.1	E5KMT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS1-AS1	ENST00000539078.2	TSL:5	n.458A>C		non_coding_transcript_exon	Exon 1 of 3
	PUS1	ENST00000376649.8	TSL:1 MANE Select	c.-534T>G		upstream_gene	N/A	ENSP00000365837.3	Q9Y606-1
	PUS1	ENST00000443358.6	TSL:1	c.-202T>G		upstream_gene	N/A	ENSP00000392451.2	Q9Y606-2

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 431 AN: 148296 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000468

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00346

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 380 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 238

African (AFR) AF: 0.00 AC: 0 AN: 26

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12

East Asian (EAS) AF: 0.00 AC: 0 AN: 20

South Asian (SAS) AF: 0.00 AC: 0 AN: 84

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 218

Other (OTH) AF: 0.00 AC: 0 AN: 18

GnomAD4 genome AF: 0.00290 AC: 431 AN: 148414 Hom.: 1 Cov.: 30 AF XY: 0.00285 AC XY: 206 AN XY: 72348

African (AFR) AF: 0.0101 AC: 410 AN: 40626

American (AMR) AF: 0.000468 AC: 7 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 4954

South Asian (SAS) AF: 0.00 AC: 0 AN: 4486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000105 AC: 7 AN: 66928

Other (OTH) AF: 0.00342 AC: 7 AN: 2048

Alfa AF: 0.00327 Hom.: 0

Bravo AF: 0.00361

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.2
CADD	Benign	5.5
DANN	Benign	0.49
PhyloP100		-0.45
PromoterAI		0.00070	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs559360646; hg19: chr12-132413734;