rs2074997

Variant names:

• chr7-151477200-C-A
• rs2074997
• NM_005614.4:c.275+133G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-151477200-C-A
• chr7-151477200-C-T

Variant summary

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

The NM_005614.4(RHEB):​c.275+133G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 656,274 control chromosomes in the GnomAD database, including 79,702 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 0.43 (15074 hom., cov: 31)
  • Exomes 𝑓: 0.50 (64628 hom.)
• Consequence: RHEB NM_005614.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.81
• Publications: 5 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHEB	NM_005614.4	c.275+133G>T		intron_variant	Intron 4 of 7	ENST00000262187.10	NP_005605.1
RHEB	XM_011516457.3	c.242+133G>T		intron_variant	Intron 5 of 8		XP_011514759.1
RHEB	XM_024446854.2	c.242+133G>T		intron_variant	Intron 5 of 8		XP_024302622.1
RHEB	XM_047420685.1	c.242+133G>T		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	c.275+133G>T		intron_variant	Intron 4 of 7	1	NM_005614.4	ENSP00000262187.5

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65290 AN: 151580 Hom.: 15063 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.435

GnomAD4 exome AF: 0.501 AC: 252736 AN: 504576 Hom.: 64628 AF XY: 0.507 AC XY: 139079 AN XY: 274310

African (AFR) AF: 0.254 AC: 2866 AN: 11280

American (AMR) AF: 0.402 AC: 6581 AN: 16366

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 10758 AN: 17616

East Asian (EAS) AF: 0.425 AC: 12402 AN: 29194

South Asian (SAS) AF: 0.586 AC: 28772 AN: 49064

European-Finnish (FIN) AF: 0.487 AC: 18405 AN: 37766

Middle Eastern (MID) AF: 0.501 AC: 1111 AN: 2218

European-Non Finnish (NFE) AF: 0.506 AC: 158356 AN: 313202

Other (OTH) AF: 0.484 AC: 13485 AN: 27870

GnomAD4 genome AF: 0.431 AC: 65324 AN: 151698 Hom.: 15074 Cov.: 31 AF XY: 0.436 AC XY: 32301 AN XY: 74090

African (AFR) AF: 0.252 AC: 10414 AN: 41330

American (AMR) AF: 0.451 AC: 6879 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2109 AN: 3464

East Asian (EAS) AF: 0.427 AC: 2202 AN: 5156

South Asian (SAS) AF: 0.598 AC: 2864 AN: 4790

European-Finnish (FIN) AF: 0.486 AC: 5110 AN: 10504

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.506 AC: 34373 AN: 67916

Other (OTH) AF: 0.437 AC: 917 AN: 2100

Alfa AF: 0.341 Hom.: 1774

Bravo AF: 0.414

Asia WGS AF: 0.487 AC: 1693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.029
DANN	Benign	0.44
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2074997; hg19: chr7-151174286; COSMIC: COSV51262897;