15-40569762-T-G

Variant names:

• chr15-40569762-T-G
• rs1891096352
• NM_152260.3:c.425T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001286407.2(RPUSD2):​c.423+2T>G variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPUSD2 NM_001286407.2 splice_donor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76
• 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_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.31752577 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.7, offset of -5, new splice context is: tgcGTaagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286407.2. 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.425T>G	p.Val142Gly	missense	Exon 1 of 3	NP_689473.1	Q8IZ73-1
	RPUSD2	NM_001286407.2		c.423+2T>G		splice_donor intron	N/A	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.425T>G	p.Val142Gly	missense	Exon 1 of 3	ENSP00000323288.7	Q8IZ73-1
	RPUSD2	ENST00000917964.1		c.425T>G	p.Val142Gly	missense	Exon 1 of 3	ENSP00000588023.1
	RPUSD2	ENST00000890562.1		c.425T>G	p.Val142Gly	missense	Exon 1 of 2	ENSP00000560621.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
PhyloP100		7.8
ClinPred		0.99	D
GERP RS		5.9
PromoterAI		0.15	Neutral
Varity_R		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1891096352; hg19: chr15-40861961;