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GeneBe

1-155900414-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_006912.6(RIT1):c.634C>T(p.Arg212Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RIT1
NM_006912.6 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.806
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 Benign. Variant got -11 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=0.054458052).
BP6
Variant 1-155900414-G-A is Benign according to our data. Variant chr1-155900414-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 280150.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000109 (160/1461564) while in subpopulation MID AF= 0.00052 (3/5764). AF 95% confidence interval is 0.000141. There are 0 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIT1NM_006912.6 linkuse as main transcriptc.634C>T p.Arg212Trp missense_variant 6/6 ENST00000368323.8
RIT1NM_001256821.2 linkuse as main transcriptc.685C>T p.Arg229Trp missense_variant 6/6
RIT1NM_001256820.2 linkuse as main transcriptc.526C>T p.Arg176Trp missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIT1ENST00000368323.8 linkuse as main transcriptc.634C>T p.Arg212Trp missense_variant 6/61 NM_006912.6 P3Q92963-1

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152076
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000716
AC:
18
AN:
251418
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000109
AC:
160
AN:
1461564
Hom.:
0
Cov.:
30
AF XY:
0.0000949
AC XY:
69
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.000344
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000116
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000900
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000273
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 24, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 23, 2018The RIT1 c.634C>T; p.Arg212Trp variant (rs563231684, ClinVar variant ID 280150), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.008% (identified on 19 out of 246,228 chromosomes). The arginine at position 212 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg212Trp variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Arg212Trp variant cannot be determined with certainty. -
Noonan syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 29, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 212 of the RIT1 protein (p.Arg212Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 280150). 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 with a negative predictive value of 95%. 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 20, 2020Variant summary: RIT1 c.634C>T (p.Arg212Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251418 control chromosomes. The observed variant frequency is approximately 5.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in RIT1 causing Noonan Syndrome And Related Conditions phenotype (1.3e-05), strongly suggesting that the variant is benign. c.634C>T has not been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions with clear evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 30, 2020This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Noonan syndrome and Noonan-related syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.34
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.31
T;.;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.86
D;D;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.054
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.3
N;N;N
REVEL
Benign
0.086
Sift
Benign
0.080
T;T;D
Sift4G
Benign
0.067
T;D;T
Polyphen
0.0020
B;.;.
Vest4
0.26
MutPred
0.38
Loss of helix (P = 0.0033);.;.;
MVP
0.37
MPC
0.81
ClinPred
0.036
T
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.056
gMVP
0.65

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: rs563231684; hg19: chr1-155870205; COSMIC: COSV64171274; COSMIC: COSV64171274; API