chr1-155904470-C-A

Variant names:

• chr1-155904470-C-A
• rs483352822
• NM_006912.6:c.270G>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_006912.6(RIT1):​c.270G>T​(p.Met90Ile) variant causes a missense change. 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M90V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.43
• Publications: 59 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

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS1: Transcript NM_006912.6 (RIT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-155904472-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 561681.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808
• PP5: Variant 1-155904470-C-A is Pathogenic according to our data. Variant chr1-155904470-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 265328.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.270G>T	p.Met90Ile	missense	Exon 5 of 6	NP_008843.1	Q92963-1
	RIT1	NM_001256821.2		c.321G>T	p.Met107Ile	missense	Exon 5 of 6	NP_001243750.1	Q92963-3
	RIT1	NM_001256820.2		c.162G>T	p.Met54Ile	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.270G>T	p.Met90Ile	missense	Exon 5 of 6	ENSP00000357306.3	Q92963-1
	RIT1	ENST00000609492.1	TSL:1	c.270G>T	p.Met90Ile	missense	Exon 4 of 5	ENSP00000476612.1	V9GYC3
	RIT1	ENST00000368322.7	TSL:3	c.321G>T	p.Met107Ile	missense	Exon 5 of 6	ENSP00000357305.3	Q92963-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Noonan syndrome 8 (3)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.095	N
PhyloP100		6.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Benign	0.076	T
Sift4G	Benign	0.094	T
Polyphen		1.0	D
Vest4		0.98
MutPred		0.62		Gain of catalytic residue at M90 (P = 0.0046)
MVP		0.65
MPC		1.9
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs483352822; hg19: chr1-155874261; COSMIC: COSV64170809;