Genetic Variant NM_006912.6:c.67A>G (chr1-155910695-T-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_006912.6(RIT1):c.67A>G(p.Lys23Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K23N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

RIT1
NM_006912.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.48

Publications

0 publications found

Variant links:

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

RIT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155910693-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3349333.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 1-155910695-T-C is Pathogenic according to our data. Variant chr1-155910695-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1695891.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIT1	NM_006912.6	MANE Select	c.67A>G	p.Lys23Glu	missense	Exon 2 of 6	NP_008843.1
RIT1	NM_001256821.2		c.118A>G	p.Lys40Glu	missense	Exon 2 of 6	NP_001243750.1
RIT1	NM_001256820.2		c.-2-189A>G		intron	N/A	NP_001243749.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIT1	ENST00000368323.8	TSL:1 MANE Select	c.67A>G	p.Lys23Glu	missense	Exon 2 of 6	ENSP00000357306.3
RIT1	ENST00000609492.1	TSL:1	c.67A>G	p.Lys23Glu	missense	Exon 1 of 5	ENSP00000476612.1
RIT1	ENST00000368322.7	TSL:3	c.118A>G	p.Lys40Glu	missense	Exon 2 of 6	ENSP00000357305.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Noonan syndrome 8

Pathogenic:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.9

PhyloP100

4.5

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.97

Vest4

0.82

MutPred

0.75

Loss of methylation at K23 (P = 0.0045)

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

4.7

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.99

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.38

Position offset: 5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over