1-155910782-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001256821.2(RIT1):c.31G>C(p.Glu11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 1,614,048 control chromosomes in the GnomAD database, including 662,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 52299 hom., cov: 33)

Exomes 𝑓: 0.91 ( 610250 hom. )

Consequence

RIT1
NM_001256821.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.4625E-7).

BP6

Variant 1-155910782-C-G is Benign according to our data. Variant chr1-155910782-C-G is described in ClinVar as Benign. ClinVar VariationId is 227047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

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>C		5_prime_UTR	Exon 2 of 6	NP_008843.1
RIT1	NM_001256821.2		c.31G>C	p.Glu11Gln	missense	Exon 2 of 6	NP_001243750.1
RIT1	NM_001256820.2		c.-2-276G>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.-21G>C		5_prime_UTR	Exon 2 of 6	ENSP00000357306.3
RIT1	ENST00000609492.1	TSL:1	c.-21G>C		5_prime_UTR	Exon 1 of 5	ENSP00000476612.1
RIT1	ENST00000368322.7	TSL:3	c.31G>C	p.Glu11Gln	missense	Exon 2 of 6	ENSP00000357305.3

Frequencies

GnomAD3 genomes

AF:

0.812

AC:

123505

AN:

152096

Hom.:

52287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.779

Gnomad AMR

AF:

0.907

Gnomad ASJ

AF:

0.875

Gnomad EAS

AF:

0.939

Gnomad SAS

AF:

0.865

Gnomad FIN

AF:

0.890

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.925

Gnomad OTH

AF:

0.844

GnomAD2 exomes

AF:

0.887

AC:

222814

AN:

251320

AF XY:

0.889

show subpopulations

Gnomad AFR exome

AF:

0.533

Gnomad AMR exome

AF:

0.945

Gnomad ASJ exome

AF:

0.874

Gnomad EAS exome

AF:

0.940

Gnomad FIN exome

AF:

0.888

Gnomad NFE exome

AF:

0.920

Gnomad OTH exome

AF:

0.890

GnomAD4 exome

AF:

0.911

AC:

1332165

AN:

1461834

Hom.:

610250

Cov.:

AF XY:

0.910

AC XY:

661997

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.527

AC:

17656

AN:

33476

American (AMR)

AF:

0.941

AC:

42058

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.877

AC:

22932

AN:

26136

East Asian (EAS)

AF:

0.945

AC:

37505

AN:

39698

South Asian (SAS)

AF:

0.856

AC:

73843

AN:

86254

European-Finnish (FIN)

AF:

0.894

AC:

47754

AN:

53408

Middle Eastern (MID)

AF:

0.829

AC:

4782

AN:

5768

European-Non Finnish (NFE)

AF:

0.928

AC:

1031807

AN:

1111984

Other (OTH)

AF:

0.891

AC:

53828

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

6886

13771

20657

27542

34428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21498

42996

64494

85992

107490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.812

AC:

123536

AN:

152214

Hom.:

52299

Cov.:

AF XY:

0.813

AC XY:

60521

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.542

AC:

22490

AN:

41464

American (AMR)

AF:

0.907

AC:

13883

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.875

AC:

3038

AN:

3472

East Asian (EAS)

AF:

0.939

AC:

4862

AN:

5176

South Asian (SAS)

AF:

0.866

AC:

4181

AN:

4828

European-Finnish (FIN)

AF:

0.890

AC:

9449

AN:

10622

Middle Eastern (MID)

AF:

0.816

AC:

240

AN:

294

European-Non Finnish (NFE)

AF:

0.925

AC:

62898

AN:

68030

Other (OTH)

AF:

0.844

AC:

1785

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1011

2022

3033

4044

5055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.889

Hom.:

19739

Bravo

AF:

0.802

TwinsUK

AF:

0.920

AC:

3413

ALSPAC

AF:

0.926

AC:

3569

ESP6500AA

AF:

0.549

AC:

2417

ESP6500EA

AF:

0.922

AC:

7926

ExAC

AF:

0.877

AC:

106464

Asia WGS

AF:

0.875

AC:

3043

AN:

3478

EpiCase

AF:

0.918

EpiControl

AF:

0.921

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Noonan syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.3

(source)

DANN

Benign

0.41

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00059

LIST_S2

Benign

0.25

MetaRNN

Benign

9.5e-7

MetaSVM

Benign

-1.1

PhyloP100

0.73

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.070

REVEL

Benign

0.062

Sift

Benign

0.43

Sift4G

Benign

0.35

Vest4

0.016

MPC

0.77

ClinPred

0.00060

GERP RS

-0.38

PromoterAI

0.027

Neutral

(source)

gMVP

0.47

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over