9-128309779-C-T

Position:

• chr9-128309779-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015679.3(TRUB2):​c.767G>A​(p.Arg256Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TRUB2 NM_015679.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

Genes affected

TRUB2 (HGNC:17170): (TruB pseudouridine synthase family member 2) 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]

TRUB2 (HGNC:):

SWI5 (HGNC:31412): (SWI5 homologous recombination repair protein) Involved in cellular response to ionizing radiation and double-strand break repair via homologous recombination. Part of Swi5-Sfr1 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34052694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRUB2	NM_015679.3	c.767G>A	p.Arg256Gln	missense_variant	8/8	ENST00000372890.6	NP_056494.1
TRUB2	NM_001329861.2	c.635G>A	p.Arg212Gln	missense_variant	7/7		NP_001316790.1
TRUB2	NM_001329862.2	c.599G>A	p.Arg200Gln	missense_variant	8/8		NP_001316791.1
TRUB2	NM_001329863.2	c.455G>A	p.Arg152Gln	missense_variant	9/9		NP_001316792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRUB2	ENST00000372890.6	c.767G>A	p.Arg256Gln	missense_variant	8/8	1	NM_015679.3	ENSP00000361982.4
TRUB2	ENST00000460320.1	n.847G>A		non_coding_transcript_exon_variant	9/9	2
SWI5	ENST00000652598.1	n.329-4051C>T		intron_variant				ENSP00000498805.2
TRUB2	ENST00000461180.1	n.*5G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251398 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135896

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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: 0.0000287 AC: 42 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727240

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74488

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000427

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

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

Sep 17, 2021

The c.767G>A (p.R256Q) alteration is located in exon 8 (coding exon 8) of the TRUB2 gene. This alteration results from a G to A substitution at nucleotide position 767, causing the arginine (R) at amino acid position 256 to be replaced by a glutamine (Q). 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	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.39
Sift	Benign	0.072	T
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.27
MPC		0.80
ClinPred		0.082	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34262454; hg19: chr9-131072058;