rs104894371

Variant names:

• chr12-131932301-C-G
• rs104894371
• NM_025215.6:c.430C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-131932301-C-G
• chr12-131932301-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_025215.6(PUS1):​c.430C>G​(p.Arg144Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUS1 NM_025215.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.82
• Publications: 9 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-131932301-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUS1	NM_025215.6	c.430C>G	p.Arg144Gly	missense_variant	Exon 3 of 6	ENST00000376649.8	NP_079491.2
PUS1	NM_001002019.3	c.346C>G	p.Arg116Gly	missense_variant	Exon 3 of 6		NP_001002019.1
PUS1	NM_001002020.3	c.346C>G	p.Arg116Gly	missense_variant	Exon 3 of 6		NP_001002020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUS1	ENST00000376649.8	c.430C>G	p.Arg144Gly	missense_variant	Exon 3 of 6	1	NM_025215.6	ENSP00000365837.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia Uncertain:1

Mar 20, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 144 of the PUS1 protein (p.Arg144Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PUS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2187061). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PUS1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg144 amino acid residue in PUS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15108122, 15971356). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;.;D;D;.;T;.;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.7	.;H;.;.;.;.;.;.;.
PhyloP100		1.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;D;.;.;.;.;.
Vest4		0.99
MutPred		0.93		.;Loss of MoRF binding (P = 0.011);.;.;.;.;Loss of MoRF binding (P = 0.011);.;.;
MVP		0.85
MPC		1.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.93
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104894371; hg19: chr12-132416846;