chr8-22994590-G-A

Variant names:

• chr8-22994590-G-A
• rs1202325516
• ENST00000519685.5:c.7G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001160036.2(RHOBTB2):​c.7G>A​(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHOBTB2 NM_001160036.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.418

Genes affected

RHOBTB2 (HGNC:18756): (Rho related BTB domain containing 2) The protein encoded by this gene is a small Rho GTPase and a candidate tumor suppressor. The encoded protein interacts with the cullin-3 protein, a ubiquitin E3 ligase necessary for mitotic cell division. This protein inhibits the growth and spread of some types of breast cancer. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

PEBP4 (HGNC:28319): (phosphatidylethanolamine binding protein 4) The phosphatidylethanolamine (PE)-binding proteins, including PEBP4, are an evolutionarily conserved family of proteins with pivotal biologic functions, such as lipid binding and inhibition of serine proteases (Wang et al., 2004 [PubMed 15302887]).[supplied by OMIM, Dec 2008]

ENSG00000245025 (HGNC:58239):

LOC107984124 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest Rho-like (size 209) in uniprot entity RHBT2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001160036.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065209925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOBTB2	NM_001160036.2	c.7G>A	p.Ala3Thr	missense_variant	Exon 3 of 12		NP_001153508.1
RHOBTB2	XM_047421607.1	c.7G>A	p.Ala3Thr	missense_variant	Exon 3 of 12		XP_047277563.1
RHOBTB2	XM_047421608.1	c.7G>A	p.Ala3Thr	missense_variant	Exon 3 of 12		XP_047277564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOBTB2	ENST00000519685.5	c.7G>A	p.Ala3Thr	missense_variant	Exon 3 of 12	1		ENSP00000427926.1
RHOBTB2	ENST00000524077.5	c.7G>A	p.Ala3Thr	missense_variant	Exon 3 of 6	3		ENSP00000430785.1
PEBP4	ENST00000522278.1	c.144+5089C>T		intron_variant	Intron 1 of 1	5		ENSP00000429414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3 of the RHOBTB2 protein (p.Ala3Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RHOBTB2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.3
DANN	Benign	0.71
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.029
Sift	Benign	0.39	T;T
Sift4G	Benign	0.39	T;T
Vest4		0.044
MutPred		0.19		Gain of phosphorylation at A3 (P = 0.0103);Gain of phosphorylation at A3 (P = 0.0103);
MVP		0.39
MPC		1.2
ClinPred		0.028	T
GERP RS		-3.1
gMVP		0.36

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1202325516; hg19: chr8-22852103;