RIT1 p.Asp125Asp

Variant names:

• chr1-155904365-G-A
• rs34831194
• NM_006912.6:c.375C>T
• RIT1 p.Asp125Asp

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB4_Strong

The NM_006912.6(RIT1):c.375C>T (p.Asp125Asp) variant causes a synonymous 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 allele was found at a cumulative frequency of 0.0013 (AC=2,103) in the gnomAD database across 1,614,028 control chromosomes, including 25 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0234. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (10 hom.)
• Consequence: RIT1 NM_006912.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.215
• Publications: 2 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: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.0234 — exceeds 1% threshold (B1 applied)
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

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>T p.Asp125Asp	synonymous	Exon 5 of 6	Prot: NP_008843.1 UniProt:
	RIT1 NM_001256821.2		c.426C>T p.Asp142Asp	synonymous	Exon 5 of 6	Prot: NP_001243750.1 UniProt:
	RIT1 NM_001256820.2		c.267C>T p.Asp89Asp	synonymous	Exon 4 of 5	Prot: NP_001243749.1 UniProt:

RIT1 NM_006912.6

MANE Select

HGVSc / HGVSpc.375C>Tp.Asp125Asp

Exon rankExon 5 of 6

synonymous

Prot: NP_008843.1UniProt: Q92963-1

RIT1 NM_001256821.2

HGVSc / HGVSpc.426C>Tp.Asp142Asp

Exon rankExon 5 of 6

synonymous

Prot: NP_001243750.1UniProt: Q92963-3

RIT1 NM_001256820.2

HGVSc / HGVSpc.267C>Tp.Asp89Asp

Exon rankExon 4 of 5

synonymous

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>T p.Asp125Asp	synonymous	Exon 5 of 6	Prot: ENSP00000357306.3 UniProt:
	RIT1 ENST00000609492.1	TSL:1	c.375C>T p.Asp125Asp	synonymous	Exon 4 of 5	Prot: ENSP00000476612.1 UniProt:
	RIT1 ENST00000368322.7	TSL:3	c.426C>T p.Asp142Asp	synonymous	Exon 5 of 6	Prot: ENSP00000357305.3 UniProt:

RIT1 ENST00000368323.8

TSL:1MANE Select

HGVSc / HGVSpc.375C>Tp.Asp125Asp

Exon rankExon 5 of 6

synonymous

Prot: ENSP00000357306.3UniProt: Q92963-1

RIT1 ENST00000609492.1

TSL:1

HGVSc / HGVSpc.375C>Tp.Asp125Asp

Exon rankExon 4 of 5

synonymous

Prot: ENSP00000476612.1UniProt: V9GYC3

RIT1 ENST00000368322.7

TSL:3

HGVSc / HGVSpc.426C>Tp.Asp142Asp

Exon rankExon 5 of 6

synonymous

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00706	AC:1074	Hom:15	AN:152134	Cov:32
GnomAD2 exomes	AF: 0.00185	AC:466	Hom:	AN:251442	Cov:
GnomAD4 exome	AF: 0.000704	AC:1029	Hom:10	AN:1461776	Cov:31
GnomAD4 genome	AF: 0.00705	AC:1074	Hom:15	AN:152252	Cov:32
TOPMed (Bravo)	AF: 0.00774	AC:2048	Hom:32	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00406	AC:411	Hom:4	AN:101126	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00598	AC:14	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00892	AC:116	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00173	AC:6	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00330	AC:6	Hom:	AN:1834	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00195	82	41954	0.00215	144	66888
SCHEMA(Schizophrenia)	0.00510	578	113366	0.00541	1034	191286

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	11
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.70
GPN-Star LLR	N/A	4.1
GPN-Star score	N/A	4.1
Mutation Taster	N/A	100/0	polymorphism
PhyloP100	Benign	0.21

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	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;

COSMIC: COSV105923350;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar