chr7-151519507-G-A

Position:

• chr7-151519507-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005614.4(RHEB):​c.5C>T​(p.Pro2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RHEB NM_005614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHEB	NM_005614.4	c.5C>T	p.Pro2Leu	missense_variant	1/8	ENST00000262187.10	NP_005605.1
RHEB	XM_011516457.3	c.-121C>T		5_prime_UTR_premature_start_codon_gain_variant	1/9		XP_011514759.1
RHEB	XM_011516457.3	c.-121C>T		5_prime_UTR_variant	1/9		XP_011514759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHEB	ENST00000262187.10	c.5C>T	p.Pro2Leu	missense_variant	1/8	1	NM_005614.4	ENSP00000262187.5
RHEB	ENST00000496004.5	c.-264+391C>T		intron_variant		2		ENSP00000418161.1
RHEB	ENST00000478470.5	n.5C>T		non_coding_transcript_exon_variant	1/9	5		ENSP00000417802.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402394 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 697016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2023

Not 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	Benign	0.30
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.38		Gain of stability (P = 0.0061);
MVP		0.71
MPC		2.3
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.76
gMVP		0.78

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: chr7-151216593;