Genetic Variant RHEB:c.275+133G>A (chr7-151477200-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005614.4(RHEB):c.275+133G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 657,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

RHEB
NM_005614.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.81

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

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

RHEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RHEB	NM_005614.4 link	c.275+133G>A	intron_variant	Intron 4 of 7	ENST00000262187.10	NP_005605.1	Q15382A0A090N900
RHEB	XM_011516457.3 link	c.242+133G>A	intron_variant	Intron 5 of 8		XP_011514759.1
RHEB	XM_024446854.2 link	c.242+133G>A	intron_variant	Intron 5 of 8		XP_024302622.1
RHEB	XM_047420685.1 link	c.242+133G>A	intron_variant	Intron 5 of 8		XP_047276641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHEB	ENST00000262187.10 link	c.275+133G>A		intron_variant	Intron 4 of 7	1	NM_005614.4	ENSP00000262187.5		Q15382

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000989

AC:

AN:

505640

Hom.:

AF XY:

0.0000109

AC XY:

AN XY:

274904

show subpopulations

African (AFR)

AF:

0.000177

AC:

AN:

11308

American (AMR)

AF:

0.00

AC:

AN:

16416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17640

East Asian (EAS)

AF:

0.00

AC:

AN:

29268

South Asian (SAS)

AF:

0.00

AC:

AN:

49134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2222

European-Non Finnish (NFE)

AF:

0.00000956

AC:

AN:

313866

Other (OTH)

AF:

0.00

AC:

AN:

27950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

AF:

0.0000132

AC:

AN:

151678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74024

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41238

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

1774

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.039

(source)

DANN

Benign

0.47

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over