chr12-131929724-T-G

Variant names:

• chr12-131929724-T-G
• NM_025215.6:c.2T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_025215.6(PUS1):​c.2T>G​(p.Met1?) variant causes a start lost 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUS1 NM_025215.6 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: -0.196

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 29 codons. Genomic position: 131929917. Lost 0.066 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-131929724-T-G is Pathogenic according to our data. Variant chr12-131929724-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3032548.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-131929724-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUS1	NM_025215.6	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	ENST00000376649.8	NP_079491.2
PUS1	NM_001002019.3	c.-10-183T>G		intron_variant	Intron 1 of 5		NP_001002019.1
PUS1	NM_001002020.3	c.-10-183T>G		intron_variant	Intron 1 of 5		NP_001002020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUS1	ENST00000376649.8	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	1	NM_025215.6	ENSP00000365837.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 1 Pathogenic:1

Feb 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PUS1-related disorder Uncertain:1

Jan 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PUS1 c.2T>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in the compound heterozygous state with a c.1156dupT (p.Ser386Phefs*36) variant in an individual with a clinical diagnosis or strong suspicion of Diamond-Blackfan anemia (Reported via chr12:132414269:T>G, Table 3, Ulirsch et al. 2018. PubMed ID: 30503522). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.013	B;.
Vest4		0.34
MutPred		0.88		Gain of methylation at M1 (P = 0.0046);Gain of methylation at M1 (P = 0.0046);
MVP		0.56
ClinPred		0.19	T
GERP RS		2.6
Varity_R		0.91
gMVP		0.82

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-132414269;