chr1-155910658-C-G

Position:

• chr1-155910658-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000368323.8(RIT1):​c.104G>C​(p.Ser35Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: RIT1 ENST00000368323.8 missense, splice_region
• Scores: Splicing: ADA: 0.8917
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000368323.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 1-155910658-C-G is Pathogenic according to our data. Variant chr1-155910658-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 183401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.104G>C	p.Ser35Thr	missense_variant, splice_region_variant	2/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.155G>C	p.Ser52Thr	missense_variant, splice_region_variant	2/6		NP_001243750.1
RIT1	NM_001256820.2	c.-2-152G>C		intron_variant			NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.104G>C	p.Ser35Thr	missense_variant, splice_region_variant	2/6	1	NM_006912.6	ENSP00000357306	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

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: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 35 of the RIT1 protein (p.Ser35Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 23791108, 25124994, 26714497, 26757980, 27101134). ClinVar contains an entry for this variant (Variation ID: 183401). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108, 27226556). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2022	Published functional studies demonstrate S35T results in enhanced ELK1 transactivation and altered GDP/GTP binding activities (Aoki et al., 2013; Fang et al. 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25049390, 27226556, 25124994, 25959749, 26757980, 26714497, 28666118, 27101134, 30898653, 29595814, 23791108) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 12, 2018	- -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 11, 2016	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2023

Variant summary: RIT1 c.104G>C (p.Ser35Thr) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251328 control chromosomes (gnomAD). c.104G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Aoki_2013, Bertola_2014, Kouz), including some cases where the variant was confirmed to have arisen de novo (Kouz_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the variant causes gain-of-function, which is a known mechanism of disease (e.g. Fang_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23791108, 25124994, 27226556, 27101134). Five ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.57	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.020	D;D;.
Sift4G	Uncertain	0.044	D;D;.
Polyphen		0.96	D;.;.
Vest4		0.82
MutPred		0.93		Loss of ubiquitination at K34 (P = 0.0896);.;Loss of ubiquitination at K34 (P = 0.0896);
MVP		0.85
MPC		1.7
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.72
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

Other links and lift over

dbSNP: rs869025189; hg19: chr1-155880449;