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GeneBe

1-155900413-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_006912.6(RIT1):c.635G>A(p.Arg212Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,760 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. R212W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

RIT1
NM_006912.6 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.48
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 Likely_benign. Variant got -5 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
BP4
Computational evidence support a benign effect (MetaRNN=0.092461884).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000592 (9/152134) while in subpopulation SAS AF= 0.000622 (3/4824). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIT1NM_006912.6 linkuse as main transcriptc.635G>A p.Arg212Gln missense_variant 6/6 ENST00000368323.8
RIT1NM_001256821.2 linkuse as main transcriptc.686G>A p.Arg229Gln missense_variant 6/6
RIT1NM_001256820.2 linkuse as main transcriptc.527G>A p.Arg176Gln missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIT1ENST00000368323.8 linkuse as main transcriptc.635G>A p.Arg212Gln missense_variant 6/61 NM_006912.6 P3Q92963-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251402
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000308
AC:
45
AN:
1461626
Hom.:
0
Cov.:
30
AF XY:
0.0000413
AC XY:
30
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000301
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Noonan syndrome 8 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMay 25, 2023This variant is present in population databases (rs764347644, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 212 of the RIT1 protein (p.Arg212Gln). This variant has not been reported in the literature in individuals affected with RIT1-related conditions. 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 performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt RIT1 function. ClinVar contains an entry for this variant (Variation ID: 1334273). -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 29, 2022The p.R212Q variant (also known as c.635G>A), located in coding exon 5 of the RIT1 gene, results from a G to A substitution at nucleotide position 635. The arginine at codon 212 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 18, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.28
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Benign
0.20
T;.;.
Eigen
Benign
-0.030
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Benign
0.0097
T
MetaRNN
Benign
0.092
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;.;.
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.86
N;N;N
REVEL
Benign
0.068
Sift
Uncertain
0.028
D;D;D
Sift4G
Benign
0.11
T;T;T
Polyphen
0.36
B;.;.
Vest4
0.32
MVP
0.53
MPC
0.90
ClinPred
0.031
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.52

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: rs764347644; hg19: chr1-155870204; COSMIC: COSV64170980; COSMIC: COSV64170980; API