rs672601335

Variant names:

• chr1-155904456-C-G
• rs672601335
• NM_006912.6:c.284G>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_006912.6(RIT1):​c.284G>C​(p.Gly95Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001190410: "In-vivo functional studies in zebrafish also support a deleterious effect of this variant." PMID:23791108" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G95G) has been classified as Likely benign. The gene RIT1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 6.43
• Publications: 21 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001190410: "In-vivo functional studies in zebrafish also support a deleterious effect of this variant." PMID:23791108; SCV002767340: "In vitro studies show that this variant results in in increased phosphorylation of ERK1/2, increased transactivation of ELK1, and enhanced protein complex formation (PMID: 23791108, 29734338)."; SCV000271447: animal models in the zebrafish have shown that this variant causes developmental anomalies similar to those seen in Noonan syndrome (Aoki 2013).; SCV000329956: Published functional studies demonstrate increased activity of the RIT1 protein compared to wild type (PMID: 23791108); Reported previously in association with Noonan spectrum disorders (PMID: 24939608).; SCV001360455: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein increases the activity of the RAS/MAPK pathway (Aoki_2013, Chen_2014).; SCV004734120: Functional studies provide conflicting evidence on the effect of this variant on RIT1 function (Aoki et al. 2013. PubMed ID: 23791108; Chen et al. 2014. PubMed ID: 25049390).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 1-155904456-C-G is Pathogenic according to our data. Variant chr1-155904456-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 60509.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.284G>C	p.Gly95Ala	missense	Exon 5 of 6	NP_008843.1	Q92963-1
	RIT1	NM_001256821.2		c.335G>C	p.Gly112Ala	missense	Exon 5 of 6	NP_001243750.1	Q92963-3
	RIT1	NM_001256820.2		c.176G>C	p.Gly59Ala	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.284G>C	p.Gly95Ala	missense	Exon 5 of 6	ENSP00000357306.3	Q92963-1
	RIT1	ENST00000609492.1	TSL:1	c.284G>C	p.Gly95Ala	missense	Exon 4 of 5	ENSP00000476612.1	V9GYC3
	RIT1	ENST00000368322.7	TSL:3	c.335G>C	p.Gly112Ala	missense	Exon 5 of 6	ENSP00000357305.3	Q92963-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Noonan syndrome 8 (8)
6	-	-	not provided (6)
3	-	-	Noonan syndrome (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome 1 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	RASopathy (1)
1	-	-	RIT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.94		Gain of sheet (P = 0.0827)
MVP		0.88
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.90
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs672601335; hg19: chr1-155874247;