1-155904365-G-T

Variant names:

• chr1-155904365-G-T
• rs34831194
• NM_006912.6:c.375C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006912.6(RIT1):​c.375C>A​(p.Asp125Glu) 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 benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D125G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.215
• Publications: 0 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: Orphanet, ClinGen
• Noonan syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10841495).

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.375C>A	p.Asp125Glu	missense	Exon 5 of 6	NP_008843.1	Q92963-1
	RIT1	NM_001256821.2		c.426C>A	p.Asp142Glu	missense	Exon 5 of 6	NP_001243750.1	Q92963-3
	RIT1	NM_001256820.2		c.267C>A	p.Asp89Glu	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.375C>A	p.Asp125Glu	missense	Exon 5 of 6	ENSP00000357306.3	Q92963-1
	RIT1	ENST00000609492.1	TSL:1	c.375C>A	p.Asp125Glu	missense	Exon 4 of 5	ENSP00000476612.1	V9GYC3
	RIT1	ENST00000368322.7	TSL:3	c.426C>A	p.Asp142Glu	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 as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	RIT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.21
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.16
Sift	Benign	0.44	T
Sift4G	Benign	0.45	T
Polyphen		0.0010	B
Vest4		0.38
MutPred		0.55		Gain of MoRF binding (P = 0.1198)
MVP		0.45
MPC		0.73
ClinPred		0.17	T
GERP RS		-0.39
Varity_R		0.13
gMVP		0.63
Mutation Taster		=82/18	polymorphism

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: rs34831194; hg19: chr1-155874156;