20-37040158-C-T

Position:

• chr20-37040158-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002895.5(RBL1):​c.1898G>A​(p.Arg633Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RBL1 NM_002895.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBL1	NM_002895.5	c.1898G>A	p.Arg633Gln	missense_variant	14/22	ENST00000373664.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBL1	ENST00000373664.8	c.1898G>A	p.Arg633Gln	missense_variant	14/22	1	NM_002895.5	P1
RBL1	ENST00000344359.7	c.1898G>A	p.Arg633Gln	missense_variant	14/21	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461036 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726740

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.1898G>A (p.R633Q) alteration is located in exon 14 (coding exon 14) of the RBL1 gene. This alteration results from a G to A substitution at nucleotide position 1898, causing the arginine (R) at amino acid position 633 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.35	T;T
Sift4G	Benign	0.40	T;T
Polyphen		1.0	D;D
Vest4		0.46
MutPred		0.20		Loss of MoRF binding (P = 0.02);Loss of MoRF binding (P = 0.02);
MVP		0.96
MPC		0.70
ClinPred		0.77	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs923766823; hg19: chr20-35668561; COSMIC: COSV60329825;