7-151471448-G-A

Position:

• chr7-151471448-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005614.4(RHEB):​c.333-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 1,563,744 control chromosomes in the GnomAD database, including 203,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20939 hom., cov: 32)
  • Exomes 𝑓: 0.51 (182786 hom.)
• Consequence: RHEB NM_005614.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002595
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18

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]

RHEB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-151471448-G-A is Benign according to our data. Variant chr7-151471448-G-A is described in ClinVar as [Benign]. Clinvar id is 1245836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-151471448-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHEB	NM_005614.4	c.333-7C>T		splice_region_variant, intron_variant		ENST00000262187.10	NP_005605.1
RHEB	XM_011516457.3	c.300-7C>T		splice_region_variant, intron_variant			XP_011514759.1
RHEB	XM_024446854.2	c.300-7C>T		splice_region_variant, intron_variant			XP_024302622.1
RHEB	XM_047420685.1	c.300-7C>T		splice_region_variant, intron_variant			XP_047276641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHEB	ENST00000262187.10	c.333-7C>T		splice_region_variant, intron_variant		1	NM_005614.4	ENSP00000262187.5

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79469 AN: 151776 Hom.: 20907 Cov.: 32

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.511

GnomAD3 exomes AF: 0.503 AC: 123250 AN: 245058 Hom.: 31699 AF XY: 0.509 AC XY: 67448 AN XY: 132444

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.447

Gnomad SAS exome AF: 0.587

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.506 AC: 714008 AN: 1411848 Hom.: 182786 Cov.: 26 AF XY: 0.509 AC XY: 358665 AN XY: 704438

Gnomad4 AFR exome AF: 0.571

Gnomad4 AMR exome AF: 0.412

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.432

Gnomad4 SAS exome AF: 0.585

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.502

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.524 AC: 79554 AN: 151896 Hom.: 20939 Cov.: 32 AF XY: 0.527 AC XY: 39078 AN XY: 74202

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.512

Alfa AF: 0.521 Hom.: 9031

Bravo AF: 0.521

Asia WGS AF: 0.509 AC: 1766 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RHEB-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as 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_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs6956899; hg19: chr7-151168534; COSMIC: COSV51262902;