rs869025309

Variant names:

• chr12-131941630-C-A
• rs869025309
• NM_025215.6:c.883C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-131941630-C-A
• chr12-131941630-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The ENST00000376649.8(PUS1):​c.883C>A​(p.Arg295Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PUS1 ENST00000376649.8 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.828
• 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 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• myopathy, lactic acidosis, and sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 12-131941630-C-A is Benign according to our data. Variant chr12-131941630-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2981609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.828 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376649.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS1	NM_025215.6	MANE Select	c.883C>A	p.Arg295Arg	synonymous	Exon 5 of 6	NP_079491.2
	PUS1	NM_001002019.3		c.799C>A	p.Arg267Arg	synonymous	Exon 5 of 6	NP_001002019.1
	PUS1	NM_001002020.3		c.799C>A	p.Arg267Arg	synonymous	Exon 5 of 6	NP_001002020.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS1	ENST00000376649.8	TSL:1 MANE Select	c.883C>A	p.Arg295Arg	synonymous	Exon 5 of 6	ENSP00000365837.3
	PUS1	ENST00000443358.6	TSL:1	c.799C>A	p.Arg267Arg	synonymous	Exon 5 of 6	ENSP00000392451.2
	PUS1	ENST00000322060.9	TSL:5	c.799C>A	p.Arg267Arg	synonymous	Exon 5 of 5	ENSP00000324726.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.34
CADD	Benign	8.2
DANN	Benign	0.59
PhyloP100		0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs869025309; hg19: chr12-132426175;