chr1-155900414-G-A

Position:

chr1-155900414-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_006912.6(RIT1):c.634C>T(p.Arg212Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RIT1
NM_006912.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.806

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a chain GTP-binding protein Rit1 (size 218) in uniprot entity RIT1_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) in NM_006912.6

BP4

Computational evidence support a benign effect (MetaRNN=0.054458052).

BP6

Variant 1-155900414-G-A is Benign according to our data. Variant chr1-155900414-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 280150.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000109 (160/1461564) while in subpopulation MID AF= 0.00052 (3/5764). AF 95% confidence interval is 0.000141. There are 0 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RIT1	NM_006912.6 linkuse as main transcript	c.634C>T	p.Arg212Trp	missense_variant	6/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2 linkuse as main transcript	c.685C>T	p.Arg229Trp	missense_variant	6/6		NP_001243750.1
RIT1	NM_001256820.2 linkuse as main transcript	c.526C>T	p.Arg176Trp	missense_variant	5/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8 linkuse as main transcript	c.634C>T	p.Arg212Trp	missense_variant	6/6	1	NM_006912.6	ENSP00000357306	P3	Q92963-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251418

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

160

AN:

1461564

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 23, 2018	The RIT1 c.634C>T; p.Arg212Trp variant (rs563231684, ClinVar variant ID 280150), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.008% (identified on 19 out of 246,228 chromosomes). The arginine at position 212 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg212Trp variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Arg212Trp variant cannot be determined with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Noonan syndrome 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 212 of the RIT1 protein (p.Arg212Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 280150). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt RIT1 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 27, 2024

Variant summary: RIT1 c.634C>T (p.Arg212Trp) results in a non-conservative amino acid change located in the Small GTPase of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251418 control chromosomes. The observed variant frequency is approximately 5.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in RIT1 causing Noonan Syndrome And Related Conditions phenotype (1.3e-05). c.634C>T has not been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions with clear evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 280150). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.086

Sift

Benign

0.080

T;T;D

Sift4G

Benign

0.067

T;D;T

Polyphen

0.0020

B;.;.

Vest4

0.26

MutPred

0.38

Loss of helix (P = 0.0033);.;.;

MVP

0.37

MPC

0.81

ClinPred

0.036

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over