NM_005614.4:c.104A>T

Variant names:

• chr7-151490963-T-A
• rs1057519950
• NM_005614.4:c.104A>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_005614.4(RHEB):​c.104A>T​(p.Tyr35Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y35L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHEB NM_005614.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.74
• Publications: 7 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a chain GTP-binding protein Rheb (size 180) in uniprot entity RHEB_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005614.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-151490962-GT-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 3238630.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.2985 (below the threshold of 3.09). Trascript score misZ: 0.028093 (below the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005614.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHEB	NM_005614.4	MANE Select	c.104A>T	p.Tyr35Phe	missense	Exon 2 of 8	NP_005605.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHEB	ENST00000262187.10	TSL:1 MANE Select	c.104A>T	p.Tyr35Phe	missense	Exon 2 of 8	ENSP00000262187.5
	RHEB	ENST00000478470.5	TSL:5	n.*52A>T		non_coding_transcript_exon	Exon 3 of 9	ENSP00000417802.1
	RHEB	ENST00000472642.5	TSL:3	c.-212A>T		5_prime_UTR	Exon 2 of 8	ENSP00000420726.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.000224 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.93		Gain of phosphorylation at T38 (P = 0.1665)
MVP		0.75
MPC		2.2
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.89
gMVP		0.83
Mutation Taster		=209/91	polymorphism

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: rs1057519950; hg19: chr7-151188049;