Variant 11-126205603-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032795.3(RPUSD4):c.661T>C(p.Ser221Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,234 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: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

RPUSD4
NM_032795.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.739

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:

RPUSD4 (HGNC:):

RPUSD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.07407683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPUSD4	NM_032795.3 linkuse as main transcript	c.661T>C	p.Ser221Pro	missense_variant	5/7	ENST00000298317.9	NP_116184.2	Q96CM3-1
RPUSD4	NM_001363516.2 linkuse as main transcript	c.661T>C	p.Ser221Pro	missense_variant	5/7		NP_001350445.1
RPUSD4	XM_011543039.3 linkuse as main transcript	c.82T>C	p.Ser28Pro	missense_variant	3/5		XP_011541341.1	B4DUN4
RPUSD4	NM_001144827.2 linkuse as main transcript	c.632-64T>C		intron_variant			NP_001138299.1	Q96CM3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPUSD4	ENST00000298317.9 linkuse as main transcript	c.661T>C	p.Ser221Pro	missense_variant	5/7	1	NM_032795.3	ENSP00000298317.4		Q96CM3-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251420

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.00000684

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

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 30, 2022

The c.661T>C (p.S221P) alteration is located in exon 5 (coding exon 5) of the RPUSD4 gene. This alteration results from a T to C substitution at nucleotide position 661, causing the serine (S) at amino acid position 221 to be replaced by a proline (P). 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

0.70

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0030

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.82

M_CAP

Benign

0.015

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.5

REVEL

Benign

0.089

Sift

Benign

0.051

Sift4G

Benign

0.074

Polyphen

0.013

Vest4

0.45

MutPred

0.48

Gain of catalytic residue at S221 (P = 0.0406);

MVP

0.29

MPC

0.25

ClinPred

0.076

GERP RS

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.73

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