16-786051-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_058192.3(RPUSD1):c.838G>T(p.Gly280Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,373,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RPUSD1 NM_058192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0460

Genes affected

RPUSD1 (HGNC:14173): (RNA pseudouridine synthase domain containing 1) Predicted to enable pseudouridine synthase activity. Predicted to be involved in enzyme-directed rRNA pseudouridine synthesis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17325935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPUSD1	NM_058192.3	c.838G>T	p.Gly280Cys	missense_variant	6/6	ENST00000007264.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPUSD1	ENST00000007264.7	c.838G>T	p.Gly280Cys	missense_variant	6/6	2	NM_058192.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000593 AC: 1 AN: 168528 Hom.: 0 AF XY: 0.0000108 AC XY: 1 AN XY: 92316

Gnomad AFR exome AF: 0.0000817

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1373280 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 673862

Gnomad4 AFR exome AF: 0.0000637

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.838G>T (p.G280C) alteration is located in exon 6 (coding exon 5) of the RPUSD1 gene. This alteration results from a G to T substitution at nucleotide position 838, causing the glycine (G) at amino acid position 280 to be replaced by a cysteine (C). 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	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T;T;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.73	N;N;N;N;N
Sift	Benign	0.039	D;D;T;T;T
Sift4G	Uncertain	0.047	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.21
MutPred		0.19		Gain of catalytic residue at P279 (P = 0.0104);Gain of catalytic residue at P279 (P = 0.0104);.;.;.;
MVP		0.40
MPC		0.44
ClinPred		0.23	T
GERP RS		3.5
Varity_R		0.079
gMVP		0.33

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: rs1282405747; hg19: chr16-836051;