rs886049091

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-131929479-G-C
• chr12-131929479-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_025215.6(PUS1):​c.-244G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 451,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: PUS1 NM_025215.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000388 (59/152246) while in subpopulation NFE AF = 0.000676 (46/68012). AF 95% confidence interval is 0.000521. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000504 AC: 151 AN: 299598 Hom.: 0 Cov.: 3 AF XY: 0.000402 AC XY: 63 AN XY: 156764

African (AFR) AF: 0.000137 AC: 1 AN: 7326

American (AMR) AF: 0.000717 AC: 6 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: 0.00 AC: 0 AN: 19108

European-Finnish (FIN) AF: 0.0000857 AC: 2 AN: 23342

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

European-Non Finnish (NFE) AF: 0.000680 AC: 128 AN: 188346

Other (OTH) AF: 0.000747 AC: 14 AN: 18744

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152246 Hom.: 0 Cov.: 31 AF XY: 0.000430 AC XY: 32 AN XY: 74442

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000385

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.72
PhyloP100		0.41
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;