7-151490948-T-A

Variant names:

• chr7-151490948-T-A
• rs1554438588
• NM_005614.4:c.119A>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_005614.4(RHEB):​c.119A>T​(p.Glu40Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHEB NM_005614.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.44

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a mutagenesis_site No effect. (size 0) in uniprot entity RHEB_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.2985 (below the threshold of 3.09). Trascript score misZ: 0.028093 (below the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 7-151490948-T-A is Pathogenic according to our data. Variant chr7-151490948-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545666.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHEB	NM_005614.4	c.119A>T	p.Glu40Val	missense_variant	Exon 2 of 8	ENST00000262187.10	NP_005605.1
RHEB	XM_011516457.3	c.86A>T	p.Glu29Val	missense_variant	Exon 3 of 9		XP_011514759.1
RHEB	XM_024446854.2	c.86A>T	p.Glu29Val	missense_variant	Exon 3 of 9		XP_024302622.1
RHEB	XM_047420685.1	c.86A>T	p.Glu29Val	missense_variant	Exon 3 of 9		XP_047276641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHEB	ENST00000262187.10	c.119A>T	p.Glu40Val	missense_variant	Exon 2 of 8	1	NM_005614.4	ENSP00000262187.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemimegalencephaly Pathogenic:1

-

Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The somatic variant c.119A> T: p.E40V in the RHEB gene has not been previously reported in public databases. We consider that this somatic variant is probably pathogenic because it is found in a highly conserved and critical residue for the tertiary structure of RHEB, therefore it could have important functional consequences (Kotyada et al., 2017). Consequences that have been confirmed in several functional models; in which, by generating hyperactivation of the RHEB protein, histopathological characteristics similar to those of cerebral cortical malformations have been observed (Sokolov et al., 2018). This is the first report of a somatic mutation in RHEB in Hemimegalencephaly and the second to report mutations in RHEB, since 2 germline mutations were recently identified in patients with impaired brain development (Reijnders et al., 2017). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.77		Loss of ubiquitination at K45 (P = 0.0702);
MVP		0.87
MPC		2.5
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.88
Mutation Taster		=183/117	disease causing (ClinVar)

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: rs1554438588; hg19: chr7-151188034; COSMIC: COSV51264604;