chr17-17793010-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_030665.4(RAI1):c.62C>T(p.Ser21Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,956 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S21S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
RAI1
NM_030665.4 missense
NM_030665.4 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 4.56
Genes affected
RAI1 (HGNC:9834): (retinoic acid induced 1) This gene is located within the Smith-Magenis syndrome region on chromosome 17. It is highly similar to its mouse counterpart and is expressed at high levels mainly in neuronal tissues. The protein encoded by this gene includes a polymorphic polyglutamine tract in the N-terminal domain. Expression of the mouse counterpart in neurons is induced by retinoic acid. This gene is associated with both the severity of the phenotype and the response to medication in schizophrenic patients. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.27551705).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAI1 | NM_030665.4 | c.62C>T | p.Ser21Leu | missense_variant | 3/6 | ENST00000353383.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAI1 | ENST00000353383.6 | c.62C>T | p.Ser21Leu | missense_variant | 3/6 | 1 | NM_030665.4 | P1 | |
RAI1 | ENST00000395774.1 | c.62C>T | p.Ser21Leu | missense_variant | 2/2 | 2 | |||
RAI1 | ENST00000471135.2 | c.62C>T | p.Ser21Leu | missense_variant | 4/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461856Hom.: 0 Cov.: 43 AF XY: 0.00000963 AC XY: 7AN XY: 727232
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 12, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAI1 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 1700394). This variant has not been reported in the literature in individuals affected with RAI1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 21 of the RAI1 protein (p.Ser21Leu). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;D;.
REVEL
Benign
Sift
Pathogenic
D;.;D;.
Sift4G
Uncertain
D;D;D;.
Polyphen
D;.;.;.
Vest4
MutPred
Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);
MVP
MPC
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at