9-128309827-T-G

Position:

• chr9-128309827-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015679.3(TRUB2):​c.719A>C​(p.His240Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRUB2 NM_015679.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRUB2	NM_015679.3	c.719A>C	p.His240Pro	missense_variant	8/8	ENST00000372890.6	NP_056494.1
TRUB2	NM_001329861.2	c.587A>C	p.His196Pro	missense_variant	7/7		NP_001316790.1
TRUB2	NM_001329862.2	c.551A>C	p.His184Pro	missense_variant	8/8		NP_001316791.1
TRUB2	NM_001329863.2	c.407A>C	p.His136Pro	missense_variant	9/9		NP_001316792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRUB2	ENST00000372890.6	c.719A>C	p.His240Pro	missense_variant	8/8	1	NM_015679.3	ENSP00000361982.4
TRUB2	ENST00000460320.1	n.799A>C		non_coding_transcript_exon_variant	9/9	2
TRUB2	ENST00000461180.1	n.517A>C		non_coding_transcript_exon_variant	2/2	2
SWI5	ENST00000652598.1	n.329-4003T>G		intron_variant				ENSP00000498805.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 10, 2022

The c.719A>C (p.H240P) alteration is located in exon 8 (coding exon 8) of the TRUB2 gene. This alteration results from a A to C substitution at nucleotide position 719, causing the histidine (H) at amino acid position 240 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	0.83
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.61		Loss of methylation at K237 (P = 0.1473);
MVP		0.33
MPC		0.95
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-131072106;