ENST00000539078.1:n.167+20G>C

Variant names:

• chr12-131929165-C-G
• rs12369083
• ENST00000539078.2:n.462+20G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000539078.2(PUS1-AS1):​n.462+20G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 150,912 control chromosomes in the GnomAD database, including 2,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2464 hom., cov: 26)
  • Exomes 𝑓: 0.0068 (0 hom.)
• Consequence: PUS1-AS1 ENST00000539078.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BP6: Variant 12-131929165-C-G is Benign according to our data. Variant chr12-131929165-C-G is described in ClinVar as Benign. ClinVar VariationId is 676183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

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.-558C>G		upstream_gene	N/A	NP_079491.2	E5KMT5
	PUS1	NM_001002019.3		c.-250C>G		upstream_gene	N/A	NP_001002019.1	E5KMT6
	PUS1	NM_001002020.3		c.-226C>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.462+20G>C		intron	N/A
	PUS1	ENST00000376649.8	TSL:1 MANE Select	c.-558C>G		upstream_gene	N/A	ENSP00000365837.3	Q9Y606-1
	PUS1	ENST00000443358.6	TSL:1	c.-226C>G		upstream_gene	N/A	ENSP00000392451.2	Q9Y606-2

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24718 AN: 150654 Hom.: 2461 Cov.: 26

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.0980

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.112

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.00685 AC: 1 AN: 146 Hom.: 0 Cov.: 0 AF XY: 0.00980 AC XY: 1 AN XY: 102

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.0161 AC: 1 AN: 62

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.164 AC: 24736 AN: 150766 Hom.: 2464 Cov.: 26 AF XY: 0.164 AC XY: 12103 AN XY: 73646

African (AFR) AF: 0.117 AC: 4824 AN: 41182

American (AMR) AF: 0.188 AC: 2848 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 738 AN: 3456

East Asian (EAS) AF: 0.521 AC: 2585 AN: 4966

South Asian (SAS) AF: 0.0977 AC: 465 AN: 4760

European-Finnish (FIN) AF: 0.151 AC: 1585 AN: 10472

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 290

European-Non Finnish (NFE) AF: 0.166 AC: 11172 AN: 67482

Other (OTH) AF: 0.160 AC: 335 AN: 2090

Alfa AF: 0.0677 Hom.: 100

Bravo AF: 0.173

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	3.3
DANN	Benign	0.44
PhyloP100		-1.1
PromoterAI		-0.068	Neutral

Splicing

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

Other links and lift over

dbSNP: rs12369083; hg19: chr12-132413710;