NM_000321.3:c.2664-10T>A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000321.3(RB1):c.2664-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,598,702 control chromosomes in the GnomAD database, including 49,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_000321.3 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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RB1 | NM_000321.3 | c.2664-10T>A | intron_variant | Intron 25 of 26 | ENST00000267163.6 | NP_000312.2 | ||
RB1 | NM_001407165.1 | c.2664-10T>A | intron_variant | Intron 25 of 26 | NP_001394094.1 | |||
RB1 | NM_001407168.1 | c.114-10T>A | intron_variant | Intron 2 of 3 | NP_001394097.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.202 AC: 30705AN: 152034Hom.: 3477 Cov.: 33
GnomAD3 exomes AF: 0.237 AC: 58755AN: 247544Hom.: 7381 AF XY: 0.241 AC XY: 32195AN XY: 133798
GnomAD4 exome AF: 0.249 AC: 360651AN: 1446550Hom.: 46321 Cov.: 30 AF XY: 0.250 AC XY: 179672AN XY: 720096
GnomAD4 genome AF: 0.202 AC: 30698AN: 152152Hom.: 3473 Cov.: 33 AF XY: 0.205 AC XY: 15222AN XY: 74362
ClinVar
Submissions by phenotype
Retinoblastoma Benign:6
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not specified Benign:4
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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not provided Benign:2
Variant summary: The RB1 c.2664-10T>A variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predict no significant impact on splicing and the creation of a ESE binding site, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 28338/108858 (3633 homozygotes, 1/3, frequency: 0.2603208), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic RB1 variant of 1/23980 (0.0000417), suggesting this variant is likely a benign polymorphism. In addition, a reputable clinical laboratory cites the variant as "benign." Taken together and based on the high allele frequency in the general population, the variant of interest is classified as Benign. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at