chr15-40569602-C-T

Variant names:

• chr15-40569602-C-T
• rs1468709735
• NM_152260.3:c.265C>T

Variant summary

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

The NM_152260.3(RPUSD2):​c.265C>T​(p.Pro89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPUSD2 NM_152260.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.182
• Publications: 0 publications found

Genes affected

RPUSD2 (HGNC:24180): (RNA pseudouridine synthase domain containing 2) Enables pseudouridine synthase activity. Involved in mRNA pseudouridine synthesis. [provided by Alliance of Genome Resources, Apr 2022]

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 (MetaRNN=0.04648143).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152260.3. 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
	RPUSD2	NM_152260.3	MANE Select	c.265C>T	p.Pro89Ser	missense	Exon 1 of 3	NP_689473.1	Q8IZ73-1
	RPUSD2	NM_001286407.2		c.265C>T	p.Pro89Ser	missense	Exon 1 of 3	NP_001273336.1	Q8IZ73-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPUSD2	ENST00000315616.12	TSL:1 MANE Select	c.265C>T	p.Pro89Ser	missense	Exon 1 of 3	ENSP00000323288.7	Q8IZ73-1
	RPUSD2	ENST00000917964.1		c.265C>T	p.Pro89Ser	missense	Exon 1 of 3	ENSP00000588023.1
	RPUSD2	ENST00000559271.1	TSL:2	c.265C>T	p.Pro89Ser	missense	Exon 1 of 3	ENSP00000453036.1	Q8IZ73-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383758 Hom.: 0 Cov.: 29 AF XY: 0.00000147 AC XY: 1 AN XY: 679686

⚠️ 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: 31960

American (AMR) AF: 0.00 AC: 0 AN: 35722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22028

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 38032

South Asian (SAS) AF: 0.00 AC: 0 AN: 75324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1072822

Other (OTH) AF: 0.00 AC: 0 AN: 57172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	0.063
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.75
DANN	Benign	0.78
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.18
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.017
Sift	Benign	0.62	T
Sift4G	Benign	0.76	T
Polyphen		0.0090	B
Vest4		0.097
MutPred		0.11		Gain of phosphorylation at P89 (P = 0.0132)
MVP		0.099
MPC		0.24
ClinPred		0.042	T
GERP RS		2.4
PromoterAI		0.15	Neutral
Varity_R		0.021
gMVP		0.18

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

dbSNP: rs1468709735; hg19: chr15-40861801;