1-155910878-C-T
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The ENST00000609492.1(RIT1):c.-117G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,585,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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
ENST00000609492.1 5_prime_UTR
ENST00000609492.1 5_prime_UTR
Scores
2
1
13
Splicing: ADA: 0.00004223
2
Clinical Significance
Conservation
PhyloP100: 0.0850
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.
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 | UniProt |
---|---|---|---|---|---|---|---|
RIT1 | NM_006912.6 | c.-43-74G>A | intron_variant | ENST00000368323.8 | |||
RIT1 | NM_001256821.2 | c.8G>A | p.Arg3Lys | missense_variant, splice_region_variant | 1/6 | ||
RIT1 | NM_001256820.2 | c.-3+365G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RIT1 | ENST00000368323.8 | c.-43-74G>A | intron_variant | 1 | NM_006912.6 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000132 AC: 26AN: 196632Hom.: 0 AF XY: 0.000169 AC XY: 18AN XY: 106350
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GnomAD4 exome AF: 0.0000502 AC: 72AN: 1433334Hom.: 0 Cov.: 39 AF XY: 0.0000534 AC XY: 38AN XY: 711006
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
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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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of methylation at R3 (P = 0.0063);
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at