dbSNP rs2282301: RIT1:c.*1554C>T (chr1-155898834-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006912.6(RIT1):c.*1554C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 191,540 control chromosomes in the GnomAD database, including 10,420 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7361 hom., cov: 30)

Exomes 𝑓: 0.34 ( 3059 hom. )

Consequence

RIT1
NM_006912.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.725

Publications

34 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6 link	c.*1554C>T	3_prime_UTR_variant	Exon 6 of 6	ENST00000368323.8	NP_008843.1	Q92963-1
RIT1	NM_001256821.2 link	c.*1554C>T	3_prime_UTR_variant	Exon 6 of 6		NP_001243750.1	Q92963-3
RIT1	NM_001256820.2 link	c.*1554C>T	3_prime_UTR_variant	Exon 5 of 5		NP_001243749.1	Q92963-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8 link	c.*1554C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_006912.6	ENSP00000357306.3		Q92963-1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44716

AN:

151550

Hom.:

7348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.317

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.752

Gnomad SAS

AF:

0.309

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.295

GnomAD4 exome

AF:

0.339

AC:

13506

AN:

39872

Hom.:

3059

Cov.:

AF XY:

0.336

AC XY:

6194

AN XY:

18428

show subpopulations

African (AFR)

AF:

0.321

AC:

517

AN:

1610

American (AMR)

AF:

0.388

AC:

397

AN:

1022

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

576

AN:

2576

East Asian (EAS)

AF:

0.749

AC:

5143

AN:

6868

South Asian (SAS)

AF:

0.305

AC:

108

AN:

354

European-Finnish (FIN)

AF:

0.206

AC:

AN:

Middle Eastern (MID)

AF:

0.159

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.244

AC:

5815

AN:

23846

Other (OTH)

AF:

0.273

AC:

904

AN:

3316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

341

682

1024

1365

1706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.295

AC:

44755

AN:

151668

Hom.:

7361

Cov.:

AF XY:

0.299

AC XY:

22120

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.317

AC:

13123

AN:

41380

American (AMR)

AF:

0.326

AC:

4953

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

786

AN:

3462

East Asian (EAS)

AF:

0.752

AC:

3885

AN:

5166

South Asian (SAS)

AF:

0.309

AC:

1489

AN:

4818

European-Finnish (FIN)

AF:

0.249

AC:

2611

AN:

10466

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.251

AC:

17069

AN:

67882

Other (OTH)

AF:

0.291

AC:

612

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1531

3062

4593

6124

7655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

448

896

1344

1792

2240

<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:

0.275

Hom.:

20825

Bravo

AF:

0.308

Asia WGS

AF:

0.514

AC:

1788

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.53

PhyloP100

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over