ENST00000519685.5:c.2T>A

Variant names:

• chr8-22994585-T-A
• rs975087060
• ENST00000519685.5:c.2T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The ENST00000519685.5(RHOBTB2):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RHOBTB2 ENST00000519685.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10

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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 19 codons. Genomic position: 22994638. Lost 0.024 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOBTB2	NM_001160036.2	c.2T>A	p.Met1?	start_lost	Exon 3 of 12		NP_001153508.1
RHOBTB2	XM_047421607.1	c.2T>A	p.Met1?	start_lost	Exon 3 of 12		XP_047277563.1
RHOBTB2	XM_047421608.1	c.2T>A	p.Met1?	start_lost	Exon 3 of 12		XP_047277564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOBTB2	ENST00000519685.5	c.2T>A	p.Met1?	start_lost	Exon 3 of 12	1		ENSP00000427926.1
RHOBTB2	ENST00000524077.5	c.2T>A	p.Met1?	start_lost	Exon 3 of 6	3		ENSP00000430785.1
PEBP4	ENST00000522278.1	c.144+5094A>T		intron_variant	Intron 1 of 1	5		ENSP00000429414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399222 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.94
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.78
MutPred		0.95		Gain of methylation at M1 (P = 0.0426);Gain of methylation at M1 (P = 0.0426);
MVP		0.53
ClinPred		0.36	T
GERP RS		3.8
gMVP		0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs975087060; hg19: chr8-22852098;