7-151490963-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_005614.4(RHEB):​c.104A>C​(p.Tyr35Ser) variant causes a missense change. 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RHEB
NM_005614.4 missense

Scores

14
3
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 7-151490963-T-G is Pathogenic according to our data. Variant chr7-151490963-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1702651.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RHEBNM_005614.4 linkuse as main transcriptc.104A>C p.Tyr35Ser missense_variant 2/8 ENST00000262187.10 NP_005605.1 Q15382A0A090N900
RHEBXM_011516457.3 linkuse as main transcriptc.71A>C p.Tyr24Ser missense_variant 3/9 XP_011514759.1
RHEBXM_024446854.2 linkuse as main transcriptc.71A>C p.Tyr24Ser missense_variant 3/9 XP_024302622.1
RHEBXM_047420685.1 linkuse as main transcriptc.71A>C p.Tyr24Ser missense_variant 3/9 XP_047276641.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RHEBENST00000262187.10 linkuse as main transcriptc.104A>C p.Tyr35Ser missense_variant 2/81 NM_005614.4 ENSP00000262187.5 Q15382

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 18, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
1.9
M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-8.8
D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.79
MutPred
0.89
Gain of disorder (P = 0.0048);
MVP
0.89
MPC
2.7
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-151188049; COSMIC: COSV51262364; API