Genetic Variant NM_005614.4:c.47C>T (chr7-151519465-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_005614.4(RHEB):c.47C>T(p.Ser16Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RHEB
NM_005614.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.97

Publications

0 publications found

Variant links:

COSMIC-nc: COSV51262962

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RHEB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a binding_site (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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005614.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHEB	NM_005614.4	MANE Select	c.47C>T	p.Ser16Phe	missense	Exon 1 of 8	NP_005605.1	A0A090N900

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHEB	ENST00000262187.10	TSL:1 MANE Select	c.47C>T	p.Ser16Phe	missense	Exon 1 of 8	ENSP00000262187.5	Q15382
RHEB	ENST00000876654.1		c.47C>T	p.Ser16Phe	missense	Exon 1 of 7	ENSP00000546713.1
RHEB	ENST00000924902.1		c.47C>T	p.Ser16Phe	missense	Exon 1 of 6	ENSP00000594961.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1380312

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685772

African (AFR)

AF:

0.00

AC:

AN:

28646

American (AMR)

AF:

0.00

AC:

AN:

37886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23732

East Asian (EAS)

AF:

0.00

AC:

AN:

32296

South Asian (SAS)

AF:

0.00

AC:

AN:

78606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3906

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072826

Other (OTH)

AF:

0.00

AC:

AN:

56216

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Seizure;C4022738:Neurodevelopmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.039

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.7

PhyloP100

5.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.62

Sift

Uncertain

0.029

Sift4G

Uncertain

0.023

Polyphen

0.16

Vest4

0.37

MutPred

0.71

Loss of phosphorylation at S16 (P = 0.0431)

MVP

0.90

MPC

1.4

ClinPred

0.77

GERP RS

2.9

PromoterAI

0.13

Neutral

(source)

Varity_R

0.68

gMVP

0.79

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over