NM_152756.5:c.4023G>C

Variant names:

• chr5-38949825-C-G
• rs746644549
• NM_152756.5:c.4023G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_152756.5(RICTOR):​c.4023G>C​(p.Met1341Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RICTOR NM_152756.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94
• 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09602237).

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.4023G>C	p.Met1341Ile	missense	Exon 31 of 38	NP_689969.2
	RICTOR	NM_001285439.2		c.4023G>C	p.Met1341Ile	missense	Exon 31 of 39	NP_001272368.1	Q6R327-3
	RICTOR	NM_001438246.1		c.3975G>C	p.Met1325Ile	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.4023G>C	p.Met1341Ile	missense	Exon 31 of 38	ENSP00000349959.3	Q6R327-1
	RICTOR	ENST00000296782.10	TSL:1	c.4023G>C	p.Met1341Ile	missense	Exon 31 of 39	ENSP00000296782.5	Q6R327-3
	RICTOR	ENST00000511516.5	TSL:1	n.*3247G>C		non_coding_transcript_exon	Exon 31 of 38	ENSP00000423019.1	Q6R327-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250276 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461348 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726990

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111600

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.048
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.17
Sift	Benign	0.41	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.21
MutPred		0.24		Gain of catalytic residue at P1343 (P = 0.0307)
MVP		0.082
MPC		0.42
ClinPred		0.21	T
GERP RS		6.0
Varity_R		0.15
gMVP		0.23
Mutation Taster		=92/8	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: rs746644549; hg19: chr5-38949927;