20-37047163-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002895.5(RBL1):c.1495C>T(p.Arg499Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000636 in 1,602,780 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000058 (1 hom.)
• Consequence: RBL1 NM_002895.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08883709).
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBL1	NM_002895.5	c.1495C>T	p.Arg499Cys	missense_variant	12/22	ENST00000373664.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBL1	ENST00000373664.8	c.1495C>T	p.Arg499Cys	missense_variant	12/22	1	NM_002895.5	P1
RBL1	ENST00000344359.7	c.1495C>T	p.Arg499Cys	missense_variant	12/21	1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000182 AC: 43 AN: 236038 Hom.: 1 AF XY: 0.000141 AC XY: 18 AN XY: 127912

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.00129

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: 0.0000363

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000579 AC: 84 AN: 1450522 Hom.: 1 Cov.: 30 AF XY: 0.0000457 AC XY: 33 AN XY: 721526

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.00150

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: 0.0000189

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000999 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000595

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

Dec 16, 2022

The c.1495C>T (p.R499C) alteration is located in exon 12 (coding exon 12) of the RBL1 gene. This alteration results from a C to T substitution at nucleotide position 1495, causing the arginine (R) at amino acid position 499 to be replaced by a cysteine (C). 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	0.083
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.089	T;T
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Benign	0.84	L;L
MutationTaster	Benign	0.57	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.42
Sift	Benign	0.13	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.014	B;B
Vest4		0.27
MVP		0.93
MPC		0.31
ClinPred		0.058	T
GERP RS		3.9
Varity_R		0.24
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs527246162; hg19: chr20-35675566;