Variant chr1-155910695-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_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

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 links:

RIT1 (HGNC:):

RIT1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a strand (size 5) in uniprot entity RIT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006912.6

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-G is described in ClinVar as [Pathogenic]. Clinvar id is 581105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 id is 1695891.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6 linkuse as main transcript	c.67A>G	p.Lys23Glu	missense_variant	2/6	ENST00000368323.8	NP_008843.1	Q92963-1
RIT1	NM_001256821.2 linkuse as main transcript	c.118A>G	p.Lys40Glu	missense_variant	2/6		NP_001243750.1	Q92963-3
RIT1	NM_001256820.2 linkuse as main transcript	c.-2-189A>G		intron_variant			NP_001243749.1	Q92963-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8 linkuse as main transcript	c.67A>G	p.Lys23Glu	missense_variant	2/6	1	NM_006912.6	ENSP00000357306.3		Q92963-1

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

Pathogenic, criteria provided, single submitter

clinical testing

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

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.9

H;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

D;D;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

0.97

D;.;.

Vest4

0.82

MutPred

0.75

Loss of methylation at K23 (P = 0.0045);.;Loss of methylation at K23 (P = 0.0045);

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over