Genetic Variant RHEB:c.276-139G>A (chr7-151471744-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005614.4(RHEB):c.276-139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 614,338 control chromosomes in the GnomAD database, including 81,380 homozygotes. 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 0.52 ( 20948 hom., cov: 33)

Exomes 𝑓: 0.51 ( 60432 hom. )

Consequence

RHEB
NM_005614.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.220

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RHEB	NM_005614.4 link	c.276-139G>A	intron_variant	Intron 4 of 7	ENST00000262187.10	NP_005605.1	Q15382A0A090N900
RHEB	XM_011516457.3 link	c.243-139G>A	intron_variant	Intron 5 of 8		XP_011514759.1
RHEB	XM_024446854.2 link	c.243-139G>A	intron_variant	Intron 5 of 8		XP_024302622.1
RHEB	XM_047420685.1 link	c.243-139G>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.276-139G>A		intron_variant	Intron 4 of 7	1	NM_005614.4	ENSP00000262187.5		Q15382

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79511

AN:

151950

Hom.:

20916

Cov.:

show subpopulations

Gnomad AFR

AF:

0.568

Gnomad AMI

AF:

0.370

Gnomad AMR

AF:

0.492

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.598

Gnomad FIN

AF:

0.486

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.509

Gnomad OTH

AF:

0.511

GnomAD4 exome

AF:

0.507

AC:

234564

AN:

462270

Hom.:

60432

Cov.:

AF XY:

0.512

AC XY:

124651

AN XY:

243622

show subpopulations

African (AFR)

AF:

0.568

AC:

6752

AN:

11892

American (AMR)

AF:

0.432

AC:

6433

AN:

14900

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

8404

AN:

13666

East Asian (EAS)

AF:

0.424

AC:

12800

AN:

30174

South Asian (SAS)

AF:

0.581

AC:

22477

AN:

38714

European-Finnish (FIN)

AF:

0.488

AC:

21712

AN:

44454

Middle Eastern (MID)

AF:

0.511

AC:

1024

AN:

2004

European-Non Finnish (NFE)

AF:

0.505

AC:

141726

AN:

280534

Other (OTH)

AF:

0.510

AC:

13236

AN:

25932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

5478

10956

16433

21911

27389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.523

AC:

79596

AN:

152068

Hom.:

20948

Cov.:

AF XY:

0.526

AC XY:

39096

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.568

AC:

23574

AN:

41468

American (AMR)

AF:

0.492

AC:

7519

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2134

AN:

3468

East Asian (EAS)

AF:

0.426

AC:

2205

AN:

5172

South Asian (SAS)

AF:

0.598

AC:

2881

AN:

4820

European-Finnish (FIN)

AF:

0.486

AC:

5143

AN:

10580

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.509

AC:

34584

AN:

67964

Other (OTH)

AF:

0.512

AC:

1083

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1978

3956

5935

7913

9891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

712

1424

2136

2848

3560

<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:

0.514

Hom.:

3714

Bravo

AF:

0.521

Asia WGS

AF:

0.512

AC:

1779

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.3

(source)

DANN

Benign

0.50

PhyloP100

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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