NM_006912.6:c.-21G>C

Variant names:

• chr1-155910782-C-G
• rs493446
• NM_006912.6:c.-21G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006912.6(RIT1):​c.-21G>C variant causes a 5 prime UTR 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. 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_006912.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.730

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 227047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155910782-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6	c.-21G>C		5_prime_UTR_variant	Exon 2 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.31G>C	p.Glu11Gln	missense_variant	Exon 2 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.-2-276G>C		intron_variant	Intron 1 of 4		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.-21G>C		5_prime_UTR_variant	Exon 2 of 6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123505 AN: 152096 Hom.: 52287 Cov.: 33

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

GnomAD3 exomes AF: 0.887 AC: 222814 AN: 251320 Hom.: 99995 AF XY: 0.889 AC XY: 120784 AN XY: 135864

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 SAS exome AF: 0.856

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.: 71 AF XY: 0.910 AC XY: 661997 AN XY: 727224

Gnomad4 AFR exome AF: 0.527

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.877

Gnomad4 EAS exome AF: 0.945

Gnomad4 SAS exome AF: 0.856

Gnomad4 FIN exome AF: 0.894

Gnomad4 NFE exome AF: 0.928

Gnomad4 OTH exome AF: 0.891

GnomAD4 genome AF: 0.812 AC: 123536 AN: 152214 Hom.: 52299 Cov.: 33 AF XY: 0.813 AC XY: 60521 AN XY: 74422

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.907

Gnomad4 ASJ AF: 0.875

Gnomad4 EAS AF: 0.939

Gnomad4 SAS AF: 0.866

Gnomad4 FIN AF: 0.890

Gnomad4 NFE AF: 0.925

Gnomad4 OTH AF: 0.844

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

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

p.Glu11Gln in exon 2 of RIT1: This variant is not expected to have clinical sign ificance because it has been identified in 45.1% (1989/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs493446). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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.-21G>C variant involves the alteration of a non-conserved nucleotide in 5-prime untranslated region of exon 2. Mutation taster predicts a benign outcome for this variant. This variant was found in 106437/121302 control chromosomes (47425 homozygotes) from ExAC at a frequency of 0.8774546, which is approximately 70196 times the estimated maximal expected allele frequency of a pathogenic RIT1 variant (0.0000125), thus it is a very common polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Because of high allele frequency in general population, this variant is classified as benign. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 8 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.3
DANN	Benign	0.41
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00059	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.062
Sift	Benign	0.43	T
Sift4G	Benign	0.35	T
Vest4		0.016
MPC		0.77
ClinPred		0.00060	T
GERP RS		-0.38
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs493446; hg19: chr1-155880573;