chr1-155904365-G-A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_StrongBP6_StrongBP7

The NM_006912.6(RIT1):c.375C>T (p.Asp125Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 ACMG Germline Pathogenicity v2019

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 -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (14/14 total B/LB).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0234 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 25.; Very high cumulative gnomAD AC = 2103 (any gene).

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