15-40571713-C-T

Variant names:

• chr15-40571713-C-T
• rs1891143233
• NM_152260.3:c.716C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152260.3(RPUSD2):​c.716C>T​(p.Ser239Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 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: 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: 7.71

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPUSD2	NM_152260.3	c.716C>T	p.Ser239Phe	missense_variant	Exon 2 of 3	ENST00000315616.12	NP_689473.1
RPUSD2	NM_001286407.2	c.533C>T	p.Ser178Phe	missense_variant	Exon 2 of 3		NP_001273336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPUSD2	ENST00000315616.12	c.716C>T	p.Ser239Phe	missense_variant	Exon 2 of 3	1	NM_152260.3	ENSP00000323288.7
RPUSD2	ENST00000559271.1	c.533C>T	p.Ser178Phe	missense_variant	Exon 2 of 3	2		ENSP00000453036.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.716C>T (p.S239F) alteration is located in exon 2 (coding exon 2) of the RPUSD2 gene. This alteration results from a C to T substitution at nucleotide position 716, causing the serine (S) at amino acid position 239 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.54		Gain of catalytic residue at S239 (P = 0.0026);.;
MVP		0.65
MPC		0.91
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs1891143233; hg19: chr15-40863912; COSMIC: COSV59766495; COSMIC: COSV59766495;