8-22995879-C-A

Variant names:

• chr8-22995879-C-A
• rs750617453
• ENST00000519685.5:c.56+1240C>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_001160037.2(RHOBTB2):​c.8C>A​(p.Ala3Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,551,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: RHOBTB2 NM_001160037.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.74

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 Likely_benign. Variant got -1 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_001160037.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007869661).
• BP6: Variant 8-22995879-C-A is Benign according to our data. Variant chr8-22995879-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3054504.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOBTB2	NM_001160037.2	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 10		NP_001153509.1
RHOBTB2	NM_001160036.2	c.56+1240C>A		intron_variant	Intron 3 of 11		NP_001153508.1
RHOBTB2	XM_047421607.1	c.56+1240C>A		intron_variant	Intron 3 of 11		XP_047277563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOBTB2	ENST00000519685.5	c.56+1240C>A		intron_variant	Intron 3 of 11	1		ENSP00000427926.1
RHOBTB2	ENST00000522948.5	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 10	5		ENSP00000429141.1
RHOBTB2	ENST00000524077.5	c.56+1240C>A		intron_variant	Intron 3 of 5	3		ENSP00000430785.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000260 AC: 40 AN: 154102 Hom.: 0 AF XY: 0.000257 AC XY: 21 AN XY: 81772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00130

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: 0.00184

GnomAD4 exome AF: 0.0000400 AC: 56 AN: 1399238 Hom.: 0 Cov.: 30 AF XY: 0.0000362 AC XY: 25 AN XY: 690136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00140

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: 9.27e-7

Gnomad4 OTH exome AF: 0.0000862

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.0000366 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

RHOBTB2-related disorder Benign:1

Jan 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.032
DANN	Benign	0.48
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.0050
Sift	Benign	0.046	D
Sift4G	Benign	0.070	T
Vest4		0.10
MutPred		0.29		Loss of MoRF binding (P = 0.0057);
MVP		0.093
ClinPred		0.072	T
GERP RS		-5.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs750617453; hg19: chr8-22853392;