NM_144709.4:c.742G>T

Variant names:

• chr2-60962872-C-A
• NM_144709.4:c.742G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144709.4(PUS10):​c.742G>T​(p.Ala248Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000706 in 1,416,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PUS10 NM_144709.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.742G>T	p.Ala248Ser	missense	Exon 9 of 18	NP_653310.2	Q3MIT2
	PUS10	NM_001322123.1		c.742G>T	p.Ala248Ser	missense	Exon 9 of 18	NP_001309052.1	Q3MIT2
	PUS10	NM_001322124.1		c.742G>T	p.Ala248Ser	missense	Exon 9 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.742G>T	p.Ala248Ser	missense	Exon 9 of 18	ENSP00000326003.6	Q3MIT2
	PUS10	ENST00000602599.1	TSL:1	n.3345G>T		non_coding_transcript_exon	Exon 7 of 16
	PUS10	ENST00000971235.1		c.766G>T	p.Ala256Ser	missense	Exon 10 of 19	ENSP00000641294.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416446 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 704952

⚠️ 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: 29162

American (AMR) AF: 0.00 AC: 0 AN: 33412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24422

East Asian (EAS) AF: 0.00 AC: 0 AN: 36404

South Asian (SAS) AF: 0.00 AC: 0 AN: 80688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095886

Other (OTH) AF: 0.00 AC: 0 AN: 58308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	0.31
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.19
Sift	Benign	0.18	T
Sift4G	Benign	0.53	T
Polyphen		0.61	P
Vest4		0.66
MutPred		0.38		Loss of helix (P = 0.028)
MVP		0.64
MPC		0.19
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.40
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-61190007;