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GeneBe

1-155900430-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_006912.6(RIT1):c.618G>C(p.Arg206Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RIT1
NM_006912.6 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0640
Variant links:
Genes affected
RIT1 (HGNC:10023): (Ras like without CAAX 1) This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a chain GTP-binding protein Rit1 (size 218) in uniprot entity RIT1_HUMAN there are 53 pathogenic changes around while only 9 benign (85%) in NM_006912.6
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15580231).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIT1NM_006912.6 linkuse as main transcriptc.618G>C p.Arg206Ser missense_variant 6/6 ENST00000368323.8
RIT1NM_001256821.2 linkuse as main transcriptc.669G>C p.Arg223Ser missense_variant 6/6
RIT1NM_001256820.2 linkuse as main transcriptc.510G>C p.Arg170Ser missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIT1ENST00000368323.8 linkuse as main transcriptc.618G>C p.Arg206Ser missense_variant 6/61 NM_006912.6 P3Q92963-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461856
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Noonan syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMar 08, 2022This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 206 of the RIT1 protein (p.Arg206Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RIT1 protein function. This variant has not been reported in the literature in individuals affected with RIT1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Benign
-0.056
T
BayesDel_noAF
Benign
-0.32
Cadd
Benign
19
Dann
Benign
0.96
DEOGEN2
Benign
0.23
T;.;.
Eigen
Benign
-0.75
Eigen_PC
Benign
-0.66
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.85
D;D;D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.23
Sift
Benign
0.076
T;T;T
Sift4G
Benign
0.15
T;T;T
Polyphen
0.34
B;.;.
Vest4
0.42
MutPred
0.29
Gain of phosphorylation at R206 (P = 0.0068);.;.;
MVP
0.62
MPC
0.90
ClinPred
0.57
D
GERP RS
-2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.090
gMVP
0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1673288777; hg19: chr1-155870221; API