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1-155900400-ATCTT-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

The NM_006912.6(RIT1):c.644_647del(p.Lys215IlefsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0001 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

RIT1
NM_006912.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.52
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0242 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BP6
Variant 1-155900400-ATCTT-A is Benign according to our data. Variant chr1-155900400-ATCTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 506383.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000164 (25/152300) while in subpopulation AMR AF= 0.000524 (8/15274). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIT1NM_006912.6 linkuse as main transcriptc.644_647del p.Lys215IlefsTer3 frameshift_variant 6/6 ENST00000368323.8
RIT1NM_001256820.2 linkuse as main transcriptc.536_539del p.Lys179IlefsTer3 frameshift_variant 5/5
RIT1NM_001256821.2 linkuse as main transcriptc.695_698del p.Lys232IlefsTer3 frameshift_variant 6/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIT1ENST00000368323.8 linkuse as main transcriptc.644_647del p.Lys215IlefsTer3 frameshift_variant 6/61 NM_006912.6 P3Q92963-1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251364
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000792
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000938
AC:
137
AN:
1461120
Hom.:
0
AF XY:
0.0000935
AC XY:
68
AN XY:
726918
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000336
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000105
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000524
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000285
Hom.:
0
Bravo
AF:
0.000253
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Noonan syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 17, 2024This sequence change creates a premature translational stop signal (p.Lys215Ilefs*3) in the RIT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the RIT1 protein. This variant is present in population databases (rs766063111, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 506383). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 02, 2023See Variant Classification Assertion Criteria. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 10, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs766063111; hg19: chr1-155870191; API