rs1749409

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_006912.6(RIT1):c.430-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 1,613,008 control chromosomes in the GnomAD database, including 662,209 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 52278 hom., cov: 32)

Exomes 𝑓: 0.91 ( 609931 hom. )

Consequence

RIT1
NM_006912.6 splice_region, intron

Scores

Splicing: ADA: 0.00001202

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.987

Publications

25 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 (BayesDel_noAF=-0.89).

BP6

Variant 1-155900625-G-A is Benign according to our data. Variant chr1-155900625-G-A is described in ClinVar as Benign. ClinVar VariationId is 181519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RIT1	NM_006912.6 link	c.430-7C>T	splice_region_variant, intron_variant	Intron 5 of 5	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2 link	c.481-7C>T	splice_region_variant, intron_variant	Intron 5 of 5		NP_001243750.1
RIT1	NM_001256820.2 link	c.322-7C>T	splice_region_variant, intron_variant	Intron 4 of 4		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8 link	c.430-7C>T		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes

AF:

0.812

AC:

123461

AN:

152038

Hom.:

52266

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:

0.886

AC:

222070

AN:

250514

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:

1331394

AN:

1460852

Hom.:

609931

Cov.:

AF XY:

0.910

AC XY:

661582

AN XY:

726698

show subpopulations

African (AFR)

AF:

0.528

AC:

17631

AN:

33386

American (AMR)

AF:

0.941

AC:

41981

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.877

AC:

22916

AN:

26116

East Asian (EAS)

AF:

0.945

AC:

37504

AN:

39698

South Asian (SAS)

AF:

0.856

AC:

73715

AN:

86098

European-Finnish (FIN)

AF:

0.894

AC:

47756

AN:

53412

Middle Eastern (MID)

AF:

0.830

AC:

4780

AN:

5762

European-Non Finnish (NFE)

AF:

0.928

AC:

1031310

AN:

1111392

Other (OTH)

AF:

0.891

AC:

53801

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

6128

12257

18385

24514

30642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21486

42972

64458

85944

107430

<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:

123492

AN:

152156

Hom.:

52278

Cov.:

AF XY:

0.813

AC XY:

60483

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.542

AC:

22482

AN:

41442

American (AMR)

AF:

0.907

AC:

13859

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.875

AC:

3038

AN:

3472

East Asian (EAS)

AF:

0.939

AC:

4877

AN:

5194

South Asian (SAS)

AF:

0.866

AC:

4180

AN:

4828

European-Finnish (FIN)

AF:

0.890

AC:

9421

AN:

10588

Middle Eastern (MID)

AF:

0.816

AC:

240

AN:

294

European-Non Finnish (NFE)

AF:

0.925

AC:

62900

AN:

68034

Other (OTH)

AF:

0.844

AC:

1785

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

961

1923

2884

3846

4807

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:

0.890

Hom.:

255506

Bravo

AF:

0.802

Asia WGS

AF:

0.875

AC:

3043

AN:

3478

EpiCase

AF:

0.918

EpiControl

AF:

0.921

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 17, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

481-7C>T in intron 5 of RIT1: This variant is not expected to have clinical sign ificance because it has been identified in 45.4% (2001/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs1749409). -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome 8

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 04, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The RIT1 c.430-7C>T variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 106445/121348 control chromosomes (47428 homozygotes) at a frequency of 0.8771879, which is approximately 70175 times the estimated maximal expected allele frequency of a pathogenic RIT1 variant (0.0000125), therefore it is a very common polymorphism found in general population. Based on the allele frequency of this variant in general population, it is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

7.5

(source)

DANN

Benign

0.52

PhyloP100

0.99

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over