1-155904365-G-T

Variant names:

• chr1-155904365-G-T
• rs34831194
• NM_006912.6:c.375C>A
• RIT1 p.Asp125Glu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_006912.6(RIT1):c.375C>A (p.Asp125Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene RIT1 is a tumor suppressor gene (CancerMine: 4 TSG, 10 oncogene, 4 driver citations). The gene RIT1 is a known oncogene (CancerMine: 4 TSG, 10 oncogene, 4 driver citations). The gene RIT1 is a cancer driver gene (CancerMine: 4 TSG, 10 oncogene, 4 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D125= (synonymous): Benign (ClinVar VariationId 197790, 2 stars); p.D125G: Uncertain_significance (ClinVar VariationId 2077068, 2 stars); p.D125N: Uncertain_significance (ClinVar VariationId 1734459, 1 star)

• 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: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

Classification according to ACGS-UK Somatic Oncogenicity v2025

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

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006912.6. You can select a different transcript below to see updated classification 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	Prot: NP_008843.1 UniProt:
	RIT1 NM_001256821.2		c.426C>A p.Asp142Glu	missense	Exon 5 of 6	Prot: NP_001243750.1 UniProt:
	RIT1 NM_001256820.2		c.267C>A p.Asp89Glu	missense	Exon 4 of 5	Prot: NP_001243749.1 UniProt:

RIT1 NM_006912.6

MANE Select

HGVSc / HGVSpc.375C>Ap.Asp125Glu

Exon rankExon 5 of 6

missense

Prot: NP_008843.1UniProt: Q92963-1

RIT1 NM_001256821.2

HGVSc / HGVSpc.426C>Ap.Asp142Glu

Exon rankExon 5 of 6

missense

Prot: NP_001243750.1UniProt: Q92963-3

RIT1 NM_001256820.2

HGVSc / HGVSpc.267C>Ap.Asp89Glu

Exon rankExon 4 of 5

missense

Prot: NP_001243749.1UniProt: Q92963-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RIT1 ENST00000368323.8	TSL:1MANE Select	c.375C>A p.Asp125Glu	missense	Exon 5 of 6	Prot: ENSP00000357306.3 UniProt:
	RIT1 ENST00000609492.1	TSL:1	c.375C>A p.Asp125Glu	missense	Exon 4 of 5	Prot: ENSP00000476612.1 UniProt:
	RIT1 ENST00000368322.7	TSL:3	c.426C>A p.Asp142Glu	missense	Exon 5 of 6	Prot: ENSP00000357305.3 UniProt:

RIT1 ENST00000368323.8

TSL:1MANE Select

HGVSc / HGVSpc.375C>Ap.Asp125Glu

Exon rankExon 5 of 6

missense

Prot: ENSP00000357306.3UniProt: Q92963-1

RIT1 ENST00000609492.1

TSL:1

HGVSc / HGVSpc.375C>Ap.Asp125Glu

Exon rankExon 4 of 5

missense

Prot: ENSP00000476612.1UniProt: V9GYC3

RIT1 ENST00000368322.7

TSL:3

HGVSc / HGVSpc.426C>Ap.Asp142Glu

Exon rankExon 5 of 6

missense

Prot: ENSP00000357305.3UniProt: Q92963-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
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
FuncVEP CTI	Benign	0.012
GPN-Star LLR	N/A	-5.1
GPN-Star score	N/A	5.1
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	82/18	polymorphism
MutationAssessor	Benign	0.20	N
PhyloP100	Benign	0.21
popEVE	Benign	-2.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.16
Sift	Benign	0.44	T
Sift4G	Benign	0.45	T
Varity_R	N/A	0.13
VESM-3B	Benign	-4.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs34831194;

hg19: chr1-155874156;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar