10-114975209-A-G

Variant summary

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

The NM_139169.5(TRUB1):c.880A>G(p.Lys294Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,458 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRUB1 NM_139169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51

Genes affected

TRUB1 (HGNC:16060): (TruB pseudouridine synthase family member 1) Pseudouridine is an abundant component of rRNAs and tRNAs and is enzymatically generated by isomerization of uridine by pseudouridine synthase (Zucchini et al., 2003 [PubMed 12736709]).[supplied by OMIM, Mar 2008]

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=0.13022333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRUB1	NM_139169.5	c.880A>G	p.Lys294Glu	missense_variant	8/8	ENST00000298746.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRUB1	ENST00000298746.5	c.880A>G	p.Lys294Glu	missense_variant	8/8	1	NM_139169.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250854 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461458 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727020

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Jan 09, 2023

The c.880A>G (p.K294E) alteration is located in exon 8 (coding exon 8) of the TRUB1 gene. This alteration results from a A to G substitution at nucleotide position 880, causing the lysine (K) at amino acid position 294 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.13
Sift	Benign	0.32	T
Sift4G	Benign	0.42	T
Polyphen		0.022	B
Vest4		0.31
MutPred		0.50		Loss of ubiquitination at K294 (P = 0.0127);
MVP		0.46
MPC		0.38
ClinPred		0.30	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.32

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: rs756221098; hg19: chr10-116734968;