Genetic Variant RIT1:c.-21G>A (chr1-155910782-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001256821.2(RIT1):c.31G>A(p.Glu11Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E11Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RIT1
NM_001256821.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.730

Publications

38 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.080357164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256821.2. 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.-21G>A		5_prime_UTR	Exon 2 of 6	NP_008843.1
RIT1	NM_001256821.2		c.31G>A	p.Glu11Lys	missense	Exon 2 of 6	NP_001243750.1
RIT1	NM_001256820.2		c.-2-276G>A		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.-21G>A		5_prime_UTR	Exon 2 of 6	ENSP00000357306.3
RIT1	ENST00000609492.1	TSL:1	c.-21G>A		5_prime_UTR	Exon 1 of 5	ENSP00000476612.1
RIT1	ENST00000368322.7	TSL:3	c.31G>A	p.Glu11Lys	missense	Exon 2 of 6	ENSP00000357305.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60394

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.7

(source)

DANN

Uncertain

0.97

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.38

M_CAP

Benign

0.018

MetaRNN

Benign

0.080

MetaSVM

Benign

-0.95

PhyloP100

0.73

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.11

REVEL

Benign

0.076

Sift

Benign

0.043

Sift4G

Benign

0.42

Vest4

0.070

MutPred

0.39

Gain of MoRF binding (P = 8e-04)

MVP

0.32

MPC

0.88

ClinPred

0.047

GERP RS

-0.38

PromoterAI

-0.017

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

gMVP

0.59

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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