rs2074997

Positions:

• chr7-151477200-C-A
• chr7-151477200-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005614.4(RHEB):​c.275+133G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 656,274 control chromosomes in the GnomAD database, including 79,702 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (15074 hom., cov: 31)
  • Exomes 𝑓: 0.50 (64628 hom.)
• Consequence: RHEB NM_005614.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.81

Genes affected

RHEB (HGNC:10011): (Ras homolog, mTORC1 binding) This gene is a member of the small GTPase superfamily and encodes a lipid-anchored, cell membrane protein with five repeats of the RAS-related GTP-binding region. This protein is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. The protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity. Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHEB	NM_005614.4	c.275+133G>T		intron_variant		ENST00000262187.10	NP_005605.1
RHEB	XM_011516457.3	c.242+133G>T		intron_variant			XP_011514759.1
RHEB	XM_024446854.2	c.242+133G>T		intron_variant			XP_024302622.1
RHEB	XM_047420685.1	c.242+133G>T		intron_variant			XP_047276641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHEB	ENST00000262187.10	c.275+133G>T		intron_variant		1	NM_005614.4	ENSP00000262187	P1

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65290 AN: 151580 Hom.: 15063 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.435

GnomAD4 exome AF: 0.501 AC: 252736 AN: 504576 Hom.: 64628 AF XY: 0.507 AC XY: 139079 AN XY: 274310

Gnomad4 AFR exome AF: 0.254

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.611

Gnomad4 EAS exome AF: 0.425

Gnomad4 SAS exome AF: 0.586

Gnomad4 FIN exome AF: 0.487

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.484

GnomAD4 genome AF: 0.431 AC: 65324 AN: 151698 Hom.: 15074 Cov.: 31 AF XY: 0.436 AC XY: 32301 AN XY: 74090

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.451

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.486

Gnomad4 NFE AF: 0.506

Gnomad4 OTH AF: 0.437

Alfa AF: 0.344 Hom.: 1746

Bravo AF: 0.414

Asia WGS AF: 0.487 AC: 1693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.029
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs2074997; hg19: chr7-151174286; COSMIC: COSV51262897;