chr7-151469166-A-C

Variant names:

• chr7-151469166-A-C
• rs717775
• NM_005614.4:c.462+1405T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005614.4(RHEB):​c.462+1405T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 151,920 control chromosomes in the GnomAD database, including 5,662 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 0.24 (5662 hom., cov: 32)
• Consequence: RHEB NM_005614.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.736
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHEB	NM_005614.4	c.462+1405T>G		intron_variant	Intron 7 of 7	ENST00000262187.10	NP_005605.1
RHEB	XM_011516457.3	c.429+1405T>G		intron_variant	Intron 8 of 8		XP_011514759.1
RHEB	XM_024446854.2	c.429+1405T>G		intron_variant	Intron 8 of 8		XP_024302622.1
RHEB	XM_047420685.1	c.429+1405T>G		intron_variant	Intron 8 of 8		XP_047276641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHEB	ENST00000262187.10	c.462+1405T>G		intron_variant	Intron 7 of 7	1	NM_005614.4	ENSP00000262187.5
RHEB	ENST00000472642.5	c.147+1405T>G		intron_variant	Intron 7 of 7	3		ENSP00000420726.1
RHEB	ENST00000496004.5	c.147+1405T>G		intron_variant	Intron 7 of 7	2		ENSP00000418161.1
RHEB	ENST00000478470.5	n.*410+1405T>G		intron_variant	Intron 8 of 8	5		ENSP00000417802.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36789 AN: 151804 Hom.: 5653 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.254

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.242 AC: 36795 AN: 151920 Hom.: 5662 Cov.: 32 AF XY: 0.251 AC XY: 18614 AN XY: 74258

African (AFR) AF: 0.0583 AC: 2407 AN: 41312

American (AMR) AF: 0.296 AC: 4524 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1143 AN: 3466

East Asian (EAS) AF: 0.413 AC: 2135 AN: 5172

South Asian (SAS) AF: 0.481 AC: 2319 AN: 4818

European-Finnish (FIN) AF: 0.311 AC: 3289 AN: 10588

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20155 AN: 67988

Other (OTH) AF: 0.253 AC: 533 AN: 2110

Alfa AF: 0.272 Hom.: 4555

Bravo AF: 0.229

Asia WGS AF: 0.410 AC: 1423 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.49
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs717775; hg19: chr7-151166252; COSMIC: COSV107259026; COSMIC: COSV107259026;