rs144588759

Variant names:

• chr2-60953955-G-A
• rs144588759
• NM_144709.4:c.1168C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_144709.4(PUS10):​c.1168C>T​(p.Arg390Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000235 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PUS10 NM_144709.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64
• Publications: 2 publications found

Genes affected

PUS10 (HGNC:26505): (pseudouridine synthase 10) Pseudouridination, the isomerization of uridine to pseudouridine, is the most common posttranscriptional nucleotide modification found in RNA and is essential for biologic functions such as spliceosome biogenesis. Pseudouridylate synthases, such as PUS10, catalyze pseudouridination of structural RNAs, including transfer, ribosomal, and splicing RNAs. These enzymes also act as RNA chaperones, facilitating the correct folding and assembly of tRNAs (McCleverty et al., 2007 [PubMed 17900615]).[supplied by OMIM, May 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144709.4. 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
	PUS10	NM_144709.4	MANE Select	c.1168C>T	p.Arg390Cys	missense	Exon 14 of 18	NP_653310.2	Q3MIT2
	PUS10	NM_001322123.1		c.1168C>T	p.Arg390Cys	missense	Exon 14 of 18	NP_001309052.1	Q3MIT2
	PUS10	NM_001322124.1		c.1168C>T	p.Arg390Cys	missense	Exon 14 of 18	NP_001309053.1	A8K6R4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUS10	ENST00000316752.11	TSL:1 MANE Select	c.1168C>T	p.Arg390Cys	missense	Exon 14 of 18	ENSP00000326003.6	Q3MIT2
	PUS10	ENST00000602599.1	TSL:1	n.3771C>T		non_coding_transcript_exon	Exon 12 of 16
	PUS10	ENST00000971235.1		c.1192C>T	p.Arg398Cys	missense	Exon 15 of 19	ENSP00000641294.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251374 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000249 AC: 364 AN: 1461624 Hom.: 0 Cov.: 30 AF XY: 0.000226 AC XY: 164 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000316 AC: 351 AN: 1111774

Other (OTH) AF: 0.000149 AC: 9 AN: 60386

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68034

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000552 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.00016	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.81
MPC		0.31
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.45
gMVP		0.71
Mutation Taster		=32/68	disease causing

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: rs144588759; hg19: chr2-61181090;