20-37020730-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002895.5(RBL1):c.2560G>A(p.Val854Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000116 in 1,560,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RBL1
NM_002895.5 missense, splice_region

Scores

Splicing: ADA: 0.7721

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61

Variant links:

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]

RBL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23222375).

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBL1	NM_002895.5 linkuse as main transcript	c.2560G>A	p.Val854Ile	missense_variant, splice_region_variant	18/22	ENST00000373664.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBL1	ENST00000373664.8 linkuse as main transcript	c.2560G>A	p.Val854Ile	missense_variant, splice_region_variant	18/22	1	NM_002895.5	P1	P28749-1
RBL1	ENST00000344359.7 linkuse as main transcript	c.2560G>A	p.Val854Ile	missense_variant, splice_region_variant	18/21	1			P28749-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000346

AC:

AN:

202556

Hom.:

AF XY:

0.0000459

AC XY:

AN XY:

108890

show subpopulations

Gnomad AFR exome

AF:

0.0000729

Gnomad AMR exome

AF:

0.0000358

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000568

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

173

AN:

1408298

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

699360

show subpopulations

Gnomad4 AFR exome

AF:

0.0000623

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000222

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000751

AC:

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

Mar 07, 2023

The c.2560G>A (p.V854I) alteration is located in exon 18 (coding exon 18) of the RBL1 gene. This alteration results from a G to A substitution at nucleotide position 2560, causing the valine (V) at amino acid position 854 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.49

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.19

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.48

P;P

Vest4

0.22

MVP

0.89

MPC

0.30

ClinPred

0.23

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.8

Varity_R

0.20

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.77

dbscSNV1_RF

Benign

0.60

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over