rs730881014

Variant names:

• chr1-155904494-A-C
• rs730881014
• NM_006912.6:c.246T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-155904494-A-C
• chr1-155904494-A-G
• chr1-155904494-A-T

Variant summary

Our verdict is Pathogenic. The variant received 30 ACMG points: 30P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006912.6(RIT1):​c.246T>G​(p.Phe82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000541750: Experimental studies have shown that this missense change affects RIT1 function (PMID:23791108, 24469055, 26714497)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F82C) has been classified as Pathogenic. The gene RIT1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 0.0180
• Publications: 39 publications found

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]

RIT1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for RIT1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 30 ACMG points.

• PS1: Transcript NM_006912.6 (RIT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000541750: Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108, 24469055, 26714497).; SCV001159742: Functional analyses of the p.Phe82Leu variant protein show increased RIT1 activity (Aoki 2013, Berger 2014, Yaoita 2016), and codon 82 lies within the functionally conserved switch II domain where many pathogenic variants in RIT1 are located (Aoki 2016).; SCV005086750: Missense variants have been functionally proven to have improved transactivation ability (PMID: 23791108).; SCV005685103: Supporting evidence of pathogenicity PS3_Supporting: literature reports that cellular experiments suggest that the variant causes impaired gene function [PMID:23791108;26714497;24469055];; SCV005900716: Experimental studies have demonstrated this variant has a gain-of-function effect on the variant protein (PMID: 23791108).; SCV000209044: Published functional studies demonstrate that p.(F82L) is a gain-of-function variant, which is an established mechanism of disease in the RIT1 gene (Aoki et al., 2013; Fang et al., 2016); SCV001432125: Functional studies report this variant has an impact on protein function and results in increased RIT1 activity in cells (Aoki_2013, Berger_2014).
• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155904495-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 372863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 1-155904494-A-C is Pathogenic according to our data. Variant chr1-155904494-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 181522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006912.6. 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
	RIT1	NM_006912.6	MANE Select	c.246T>G	p.Phe82Leu	missense	Exon 5 of 6	NP_008843.1	Q92963-1
	RIT1	NM_001256821.2		c.297T>G	p.Phe99Leu	missense	Exon 5 of 6	NP_001243750.1	Q92963-3
	RIT1	NM_001256820.2		c.138T>G	p.Phe46Leu	missense	Exon 4 of 5	NP_001243749.1	Q92963-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIT1	ENST00000368323.8	TSL:1 MANE Select	c.246T>G	p.Phe82Leu	missense	Exon 5 of 6	ENSP00000357306.3	Q92963-1
	RIT1	ENST00000609492.1	TSL:1	c.246T>G	p.Phe82Leu	missense	Exon 4 of 5	ENSP00000476612.1	V9GYC3
	RIT1	ENST00000368322.7	TSL:3	c.297T>G	p.Phe99Leu	missense	Exon 5 of 6	ENSP00000357305.3	Q92963-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Noonan syndrome 8 (10)
4	-	-	not provided (4)
1	-	-	Non-immune hydrops fetalis (1)
1	-	-	Noonan syndrome (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Noonan syndrome;C0152021:Congenital heart disease (1)
1	-	-	RASopathy (1)
1	-	-	RIT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.042	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.018
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.026	D
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.87		Gain of helix (P = 0.132)
MVP		0.94
MPC		2.0
ClinPred		0.98	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730881014; hg19: chr1-155874285; COSMIC: COSV64170802;