Genetic Variant RPUSD3:p.Val105Leu (chr3-9842053-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173659.5(RPUSD3):c.313G>C(p.Val105Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RPUSD3
NM_173659.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Publications

0 publications found

Variant links:

Genes affected

RPUSD3 (HGNC:28437): (RNA pseudouridine synthase D3) This gene encodes a protein that functions in the assembly of the mitochondrial ribosome by adding a pseudouridine group to 16S rRNA. Loss of this gene results in causes defects in mitochondrial protein production. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2017]

RPUSD3 links:

TTLL3 (HGNC:24483): (tubulin tyrosine ligase like 3) Enables protein-glycine ligase activity. Predicted to be involved in axoneme assembly and flagellated sperm motility. Predicted to be located in axoneme; microtubule cytoskeleton; and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

TTLL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23329654).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173659.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPUSD3	NM_173659.5	MANE Select	c.313G>C	p.Val105Leu	missense	Exon 4 of 9	NP_775930.3	Q6P087-5
RPUSD3	NM_001142547.3		c.268G>C	p.Val90Leu	missense	Exon 3 of 8	NP_001136019.2	Q6P087-6
RPUSD3	NM_001351738.2		c.313G>C	p.Val105Leu	missense	Exon 4 of 9	NP_001338667.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPUSD3	ENST00000383820.10	TSL:1 MANE Select	c.313G>C	p.Val105Leu	missense	Exon 4 of 9	ENSP00000373331.6	Q6P087-5
RPUSD3	ENST00000433535.7	TSL:1	c.268G>C	p.Val90Leu	missense	Exon 3 of 8	ENSP00000398921.3	Q6P087-6
RPUSD3	ENST00000923702.1		c.439G>C	p.Val147Leu	missense	Exon 5 of 10	ENSP00000593761.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249996

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459856

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110780

Other (OTH)

AF:

0.00

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0089

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.091

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.80

M_CAP

Benign

0.015

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

PhyloP100

3.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

REVEL

Benign

0.057

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.77

Vest4

0.26

MutPred

0.48

Loss of helix (P = 0.1299)

MVP

0.48

MPC

0.30

ClinPred

0.22

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.077

gMVP

0.32

Mutation Taster

=84/16

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over