chr20-37040216-T-C
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_002895.5(RBL1):c.1840A>G(p.Met614Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,614,024 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000081 ( 1 hom. )
Consequence
RBL1
NM_002895.5 missense
NM_002895.5 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: -0.418
Genes affected
RBL1 (HGNC:9893): (RB transcriptional corepressor like 1) The protein encoded by this gene is similar in sequence and possibly function to the product of the retinoblastoma 1 (RB1) gene. The RB1 gene product is a tumor suppressor protein that appears to be involved in cell cycle regulation, as it is phosphorylated in the S to M phase transition and is dephosphorylated in the G1 phase of the cell cycle. Both the RB1 protein and the product of this gene can form a complex with adenovirus E1A protein and SV40 large T-antigen, with the SV40 large T-antigen binding only to the unphosphorylated form of each protein. In addition, both proteins can inhibit the transcription of cell cycle genes containing E2F binding sites in their promoters. Due to the sequence and biochemical similarities with the RB1 protein, it is thought that the protein encoded by this gene may also be a tumor suppressor. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.040952444).
BS2
?
High AC in GnomAd at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RBL1 | NM_002895.5 | c.1840A>G | p.Met614Val | missense_variant | 14/22 | ENST00000373664.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RBL1 | ENST00000373664.8 | c.1840A>G | p.Met614Val | missense_variant | 14/22 | 1 | NM_002895.5 | P1 | |
RBL1 | ENST00000344359.7 | c.1840A>G | p.Met614Val | missense_variant | 14/21 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000111 AC: 28AN: 251408Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135876
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GnomAD4 exome AF: 0.0000814 AC: 119AN: 1461830Hom.: 1 Cov.: 31 AF XY: 0.000102 AC XY: 74AN XY: 727218
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GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74358
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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 | Ambry Genetics | Jan 05, 2022 | The c.1840A>G (p.M614V) alteration is located in exon 14 (coding exon 14) of the RBL1 gene. This alteration results from a A to G substitution at nucleotide position 1840, causing the methionine (M) at amino acid position 614 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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