rs1749409

chr1-155900625-G-Achr1-155900625-G-T

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.430-7C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001202
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.987

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 (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 id is 181519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155900625-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIT1	NM_006912.6	c.430-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000368323.8
RIT1	NM_001256820.2	c.322-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RIT1	NM_001256821.2	c.481-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIT1	ENST00000368323.8	c.430-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006912.6	P3

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123461 AN: 152038 Hom.: 52266 Cov.: 32

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: 0.886 AC: 222070 AN: 250514 Hom.: 99654 AF XY: 0.889 AC XY: 120380 AN XY: 135402

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: 1331394 AN: 1460852 Hom.: 609931 Cov.: 37 AF XY: 0.910 AC XY: 661582 AN XY: 726698

Gnomad4 AFR exome AF: 0.528

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: 123492 AN: 152156 Hom.: 52278 Cov.: 32 AF XY: 0.813 AC XY: 60483 AN XY: 74392

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: 0.902 Hom.: 124151

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Noonan syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 04, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	7.5
Dann	Benign	0.52

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

LitVar

Other links and lift over

dbSNP: rs1749409; hg19: chr1-155870416;