Genetic Variant RIT1:p.Lys23Gln (chr1-155910695-T-G) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_006912.6(RIT1):c.67A>C(p.Lys23Gln) 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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U: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: Pathogenic. The variant received 14 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, 0.894

PP5

Variant 1-155910695-T-G is Pathogenic according to our data. Variant chr1-155910695-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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>C	p.Lys23Gln	missense	Exon 2 of 6	NP_008843.1
RIT1	NM_001256821.2		c.118A>C	p.Lys40Gln	missense	Exon 2 of 6	NP_001243750.1
RIT1	NM_001256820.2		c.-2-189A>C		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>C	p.Lys23Gln	missense	Exon 2 of 6	ENSP00000357306.3
RIT1	ENST00000609492.1	TSL:1	c.67A>C	p.Lys23Gln	missense	Exon 1 of 5	ENSP00000476612.1
RIT1	ENST00000368322.7	TSL:3	c.118A>C	p.Lys40Gln	missense	Exon 2 of 6	ENSP00000357305.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Noonan syndrome 8 (2)

Cardiovascular phenotype (1)

Hypertelorism;C0239340:Pedal edema;C0349588:Short stature;C0423110:Downslanted palpebral fissures (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.3

PhyloP100

4.5

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.81

MutPred

0.73

Loss of methylation at K23 (P = 0.0045)

MVP

0.94

MPC

1.9

ClinPred

0.99

GERP RS

4.7

PromoterAI

0.0086

Neutral

(source)

Varity_R

0.94

gMVP

0.98

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Computational scores

Splicing

Publications

Other links and lift over