NM_025215.6:c.2T>G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong 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
• 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-AS1 (HGNC:40706): (PUS1 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 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 VariationId is 3032548.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025215.6. 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.2T>G	p.Met1?	start_lost	Exon 1 of 6	NP_079491.2	E5KMT5
	PUS1	NM_001002019.3		c.-10-183T>G		intron	N/A	NP_001002019.1	E5KMT6
	PUS1	NM_001002020.3		c.-10-183T>G		intron	N/A	NP_001002020.1	E5KMT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS1	ENST00000376649.8	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000365837.3	Q9Y606-1
	PUS1	ENST00000443358.6	TSL:1	c.-10-183T>G		intron	N/A	ENSP00000392451.2	Q9Y606-2
	PUS1	ENST00000890860.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000560919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Myopathy, lactic acidosis, and sideroblastic anemia 1 (1)
-	1	-	PUS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.97	T
PhyloP100		-0.20
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.013	B
Vest4		0.34
MutPred		0.88		Gain of methylation at M1 (P = 0.0046)
MVP		0.56
ClinPred		0.19	T
GERP RS		2.6
PromoterAI		-0.053	Neutral
Varity_R		0.91
gMVP		0.82
Mutation Taster		=76/124	disease causing

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

hg19: chr12-132414269;