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.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_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 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 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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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