7-151470644-C-G

Variant names:

Variant summary

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

The NM_005614.4(RHEB):c.389G>C(p.Ser130Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RHEB
NM_005614.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a modified_residue Phosphoserine; by MAPKAPK5 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHEB	NM_005614.4 link	c.389G>C	p.Ser130Thr	missense_variant	Exon 7 of 8	ENST00000262187.10	NP_005605.1	Q15382A0A090N900
RHEB	XM_011516457.3 link	c.356G>C	p.Ser119Thr	missense_variant	Exon 8 of 9		XP_011514759.1
RHEB	XM_024446854.2 link	c.356G>C	p.Ser119Thr	missense_variant	Exon 8 of 9		XP_024302622.1
RHEB	XM_047420685.1 link	c.356G>C	p.Ser119Thr	missense_variant	Exon 8 of 9		XP_047276641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHEB	ENST00000262187.10 link	c.389G>C	p.Ser130Thr	missense_variant	Exon 7 of 8	1	NM_005614.4	ENSP00000262187.5		Q15382

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249814

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33360

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44552

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26084

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39652

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

85886

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53390

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1108188

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60196

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.389G>C (p.S130T) alteration is located in exon 7 (coding exon 7) of the RHEB gene. This alteration results from a G to C substitution at nucleotide position 389, causing the serine (S) at amino acid position 130 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.59

D;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

T;.;D

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.20

N;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.6

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.54

T;T;T

Polyphen

0.015

B;.;.

Vest4

0.55

MutPred

0.48

Loss of disorder (P = 0.079);.;.;

MVP

0.85

MPC

1.1

ClinPred

0.46

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.84

Mutation Taster

=39/61

disease causing

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over