5-38949766-G-C

Variant names:

• chr5-38949766-G-C
• rs141067436
• NM_152756.5:c.4082C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_152756.5(RICTOR):​c.4082C>G​(p.Thr1361Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,006 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1361I) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RICTOR NM_152756.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56
• Publications: 1 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 3 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.

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.4082C>G	p.Thr1361Ser	missense	Exon 31 of 38	NP_689969.2
	RICTOR	NM_001285439.2		c.4082C>G	p.Thr1361Ser	missense	Exon 31 of 39	NP_001272368.1	Q6R327-3
	RICTOR	NM_001438246.1		c.4034C>G	p.Thr1345Ser	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.4082C>G	p.Thr1361Ser	missense	Exon 31 of 38	ENSP00000349959.3	Q6R327-1
	RICTOR	ENST00000296782.10	TSL:1	c.4082C>G	p.Thr1361Ser	missense	Exon 31 of 39	ENSP00000296782.5	Q6R327-3
	RICTOR	ENST00000511516.5	TSL:1	n.*3306C>G		non_coding_transcript_exon	Exon 31 of 38	ENSP00000423019.1	Q6R327-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.81	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.28
Sift	Benign	0.25	T
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.65
MutPred		0.26		Loss of sheet (P = 0.0357)
MVP		0.28
MPC		1.1
ClinPred		0.65	D
GERP RS		6.0
Varity_R		0.12
gMVP		0.40
Mutation Taster		=49/51	disease causing

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: rs141067436; hg19: chr5-38949868;