rs750911924
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_030665.4(RAI1):c.3895G>A(p.Asp1299Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1299A) has been classified as Uncertain significance.
Frequency
Consequence
NM_030665.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAI1 | NM_030665.4 | c.3895G>A | p.Asp1299Asn | missense_variant | 3/6 | ENST00000353383.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAI1 | ENST00000353383.6 | c.3895G>A | p.Asp1299Asn | missense_variant | 3/6 | 1 | NM_030665.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249394Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135216
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1459964Hom.: 0 Cov.: 37 AF XY: 0.0000151 AC XY: 11AN XY: 726122
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74346
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 28, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1299 of the RAI1 protein (p.Asp1299Asn). This variant is present in population databases (rs750911924, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 436500). 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 with a negative predictive value of 80%. 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. - |
Smith-Magenis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
RAI1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 14, 2023 | The RAI1 c.3895G>A variant is predicted to result in the amino acid substitution p.Asp1299Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17700157-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at