rs1347755761
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000321.3(RB1):āc.356A>Cā(p.Glu119Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E119D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.356A>C | p.Glu119Ala | missense_variant | 3/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.356A>C | p.Glu119Ala | missense_variant | 3/27 | ||
RB1 | NM_001407166.1 | c.356A>C | p.Glu119Ala | missense_variant | 3/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.356A>C | p.Glu119Ala | missense_variant | 3/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.138-17327A>C | intron_variant, NMD_transcript_variant | 1 | |||||
RB1 | ENST00000650461.1 | c.356A>C | p.Glu119Ala | missense_variant | 3/27 | ||||
RB1 | ENST00000525036.1 | n.518A>C | non_coding_transcript_exon_variant | 3/7 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251068Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135726
GnomAD4 exome Cov.: 29
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2020 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RB1-related disease. This sequence change replaces glutamic acid with alanine at codon 119 of the RB1 protein (p.Glu119Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2020 | The p.E119A variant (also known as c.356A>C), located in coding exon 3 of the RB1 gene, results from an A to C substitution at nucleotide position 356. The glutamic acid at codon 119 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at