5-38949952-C-A

Variant names:

• chr5-38949952-C-A
• rs2112848829
• NM_152756.5:c.3896G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_152756.5(RICTOR):​c.3896G>T​(p.Arg1299Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R1299K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RICTOR NM_152756.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

Genes affected

RICTOR (HGNC:28611): (RPTOR independent companion of MTOR complex 2) RICTOR and MTOR (FRAP1; MIM 601231) are components of a protein complex that integrates nutrient- and growth factor-derived signals to regulate cell growth (Sarbassov et al., 2004 [PubMed 15268862]).[supplied by OMIM, Mar 2008]

RICTOR Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.0542 (below the threshold of 3.09). Trascript score misZ: 2.7182 (below the threshold of 3.09). GenCC associations: The gene is linked to Tourette syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152756.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RICTOR	NM_152756.5	MANE Select	c.3896G>T	p.Arg1299Ile	missense	Exon 31 of 38	NP_689969.2
	RICTOR	NM_001285439.2		c.3896G>T	p.Arg1299Ile	missense	Exon 31 of 39	NP_001272368.1	Q6R327-3
	RICTOR	NM_001438246.1		c.3848G>T	p.Arg1283Ile	missense	Exon 30 of 38	NP_001425175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RICTOR	ENST00000357387.8	TSL:1 MANE Select	c.3896G>T	p.Arg1299Ile	missense	Exon 31 of 38	ENSP00000349959.3	Q6R327-1
	RICTOR	ENST00000296782.10	TSL:1	c.3896G>T	p.Arg1299Ile	missense	Exon 31 of 39	ENSP00000296782.5	Q6R327-3
	RICTOR	ENST00000511516.5	TSL:1	n.*3120G>T		non_coding_transcript_exon	Exon 31 of 38	ENSP00000423019.1	Q6R327-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.90	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.38		Loss of phosphorylation at S1302 (P = 0.0521)
MVP		0.24
MPC		1.6
ClinPred		0.93	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.59
Mutation Taster		=82/18	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: rs2112848829; hg19: chr5-38950054;