12-131929479-G-T

Variant names:

• chr12-131929479-G-T
• rs886049091
• NM_025215.6:c.-244G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025215.6(PUS1):​c.-244G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000668 in 299,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: PUS1 NM_025215.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.415
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

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.-244G>T		5_prime_UTR	Exon 1 of 6	NP_079491.2	E5KMT5
	PUS1	NM_001002019.3		c.-11+75G>T		intron	N/A	NP_001002019.1	E5KMT6
	PUS1	NM_001002020.3		c.-11+99G>T		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.-244G>T		5_prime_UTR	Exon 1 of 6	ENSP00000365837.3	Q9Y606-1
	PUS1	ENST00000443358.6	TSL:1	c.-11+99G>T		intron	N/A	ENSP00000392451.2	Q9Y606-2
	PUS1	ENST00000890860.1		c.-244G>T		5_prime_UTR	Exon 1 of 6	ENSP00000560919.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000668 AC: 2 AN: 299600 Hom.: 0 Cov.: 3 AF XY: 0.0000128 AC XY: 2 AN XY: 156764

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7326

American (AMR) AF: 0.00 AC: 0 AN: 8366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9968

East Asian (EAS) AF: 0.00 AC: 0 AN: 22924

South Asian (SAS) AF: 0.000105 AC: 2 AN: 19108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1474

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 188348

Other (OTH) AF: 0.00 AC: 0 AN: 18744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.1
DANN	Benign	0.74
PhyloP100		0.41
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs886049091; hg19: chr12-132414024;