Variant chr11-126205758-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032795.3(RPUSD4):c.581T>C(p.Met194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,610,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

RPUSD4
NM_032795.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

Variant links:

Genes affected

RPUSD4 (HGNC:25898): (RNA pseudouridine synthase D4) Enables mitochondrial ribosomal large subunit rRNA binding activity; pseudouridine synthase activity; and tRNA binding activity. Involved in mitochondrial tRNA pseudouridine synthesis and positive regulation of mitochondrial translation. Located in mitochondrion; nucleoplasm; and ribonucleoprotein granule. [provided by Alliance of Genome Resources, Apr 2022]

RPUSD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033022374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RPUSD4	NM_032795.3 linkuse as main transcript	c.581T>C	p.Met194Thr	missense_variant	4/7	ENST00000298317.9
RPUSD4	XM_011543039.3 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/5
RPUSD4	NM_001363516.2 linkuse as main transcript	c.581T>C	p.Met194Thr	missense_variant	4/7
RPUSD4	NM_001144827.2 linkuse as main transcript	c.581T>C	p.Met194Thr	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPUSD4	ENST00000298317.9 linkuse as main transcript	c.581T>C	p.Met194Thr	missense_variant	4/7	1	NM_032795.3	P1	Q96CM3-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152226

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000113

AC:

AN:

246934

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

133436

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000473

Gnomad NFE exome

AF:

0.000242

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000624

AC:

AN:

1458592

Hom.:

Cov.:

AF XY:

0.0000621

AC XY:

AN XY:

725146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000188

Gnomad4 NFE exome

AF:

0.0000793

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000867

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.581T>C (p.M194T) alteration is located in exon 4 (coding exon 4) of the RPUSD4 gene. This alteration results from a T to C substitution at nucleotide position 581, causing the methionine (M) at amino acid position 194 to be replaced by a threonine (T). 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

0.085

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.5

DANN

Benign

0.79

DEOGEN2

Benign

0.00047

T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.63

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.25

N;N

REVEL

Benign

0.048

Sift

Benign

0.57

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.0

B;.

Vest4

0.16

MVP

0.25

MPC

0.17

ClinPred

0.039

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over