Genetic Variant CTU1:p.Arg296Ser (chr19-51098762-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_145232.4(CTU1):c.886C>A(p.Arg296Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000377 in 1,114,314 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CTU1
NM_145232.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58

Variant links:

Genes affected

CTU1 (HGNC:29590): (cytosolic thiouridylase subunit 1) Predicted to enable tRNA binding activity. Predicted to be involved in tRNA wobble position uridine thiolation. Predicted to be located in cytosol. Predicted to be part of cytosolic tRNA wobble base thiouridylase complex. [provided by Alliance of Genome Resources, Apr 2022]

CTU1 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=0.065588504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTU1	NM_145232.4 link	c.886C>A	p.Arg296Ser	missense_variant	Exon 3 of 3	ENST00000421832.3	NP_660275.2	Q7Z7A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTU1	ENST00000421832.3 link	c.886C>A	p.Arg296Ser	missense_variant	Exon 3 of 3	2	NM_145232.4	ENSP00000390011.1		Q7Z7A3

Frequencies

GnomAD3 genomes

AF:

0.0000474

AC:

AN:

147640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00176

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000362

AC:

AN:

966674

Hom.:

Cov.:

AF XY:

0.0000351

AC XY:

AN XY:

455420

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00314

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000591

Gnomad4 OTH exome

AF:

0.0000282

GnomAD4 genome

AF:

0.0000474

AC:

AN:

147640

Hom.:

Cov.:

AF XY:

0.0000417

AC XY:

AN XY:

71882

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00176

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.886C>A (p.R296S) alteration is located in exon 3 (coding exon 2) of the CTU1 gene. This alteration results from a C to A substitution at nucleotide position 886, causing the arginine (R) at amino acid position 296 to be replaced by a serine (S). 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

0.32

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0054

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

M_CAP

Benign

0.049

MetaRNN

Benign

0.066

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.48

REVEL

Benign

0.035

Sift

Benign

0.073

Sift4G

Benign

0.29

Polyphen

0.10

Vest4

0.21

MutPred

0.38

Loss of MoRF binding (P = 0.0202);

MVP

0.14

MPC

1.3

ClinPred

0.35

GERP RS

2.4

Varity_R

0.15

gMVP

0.40

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