rs730881012

Positions:

chr1-155910878-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_001256821.2(RIT1):c.8G>A(p.Arg3Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,585,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

RIT1
NM_001256821.2 missense, splice_region

Scores

Splicing: ADA: 0.00004223

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0850

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a chain GTP-binding protein Rit1 (size 218) in uniprot entity RIT1_HUMAN there are 55 pathogenic changes around while only 11 benign (83%) in NM_001256821.2

BP4

Computational evidence support a benign effect (MetaRNN=0.07235709).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000502 (72/1433334) while in subpopulation MID AF= 0.000523 (3/5740). AF 95% confidence interval is 0.000321. There are 0 homozygotes in gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 39. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6 link	c.-43-74G>A		intron_variant		ENST00000368323.8	NP_008843.1	Q92963-1
RIT1	NM_001256821.2 link	c.8G>A	p.Arg3Lys	missense_variant, splice_region_variant	1/6		NP_001243750.1	Q92963-3
RIT1	NM_001256820.2 link	c.-3+365G>A		intron_variant			NP_001243749.1	Q92963-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8 link	c.-43-74G>A		intron_variant		1	NM_006912.6	ENSP00000357306.3		Q92963-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000132

AC:

AN:

196632

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

106350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000542

Gnomad ASJ exome

AF:

0.000110

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000606

Gnomad OTH exome

AF:

0.000383

GnomAD4 exome

AF:

0.0000502

AC:

AN:

1433334

Hom.:

Cov.:

AF XY:

0.0000534

AC XY:

AN XY:

711006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000489

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000954

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000337

Gnomad4 OTH exome

AF:

0.0000673

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.0000933

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 26, 2016

The p.Arg3Lys variant in RIT1 has not been previously reported in individuals wi th Noonan spectrum disorders, but has been identified in 8/49232 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 730881012). This variant is located in the last base of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicin g or an impact to the protein. However, this information is not predictive enoug h to rule out pathogenicity. In summary, the clinical significance of the p.Arg3 Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.1

DANN

Benign

0.91

Eigen

Benign

0.055

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.34

M_CAP

Benign

0.0076

MetaRNN

Benign

0.072

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.20

REVEL

Benign

0.0080

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.11

MutPred

0.36

Gain of methylation at R3 (P = 0.0063);

MVP

0.44

MPC

0.79

ClinPred

0.043

GERP RS

-1.3

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000042

dbscSNV1_RF

Benign

0.062

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

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