20-37047099-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Moderate BP6_Moderate BS2

The NM_002895.5(RBL1):c.1559C>G(p.Pro520Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,598,378 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: RBL1 NM_002895.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.65

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 Benign. Variant got -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.07501322).
• BP6: Variant 20-37047099-G-C is Benign according to our data. Variant chr20-37047099-G-C is described in ClinVar as [Benign]. Clinvar id is 721599.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 335 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBL1	NM_002895.5	c.1559C>G	p.Pro520Arg	missense_variant	12/22	ENST00000373664.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBL1	ENST00000373664.8	c.1559C>G	p.Pro520Arg	missense_variant	12/22	1	NM_002895.5	P1
RBL1	ENST00000344359.7	c.1559C>G	p.Pro520Arg	missense_variant	12/21	1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152008 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

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: 0.000478

GnomAD3 exomes AF: 0.000587 AC: 138 AN: 235016 Hom.: 0 AF XY: 0.000440 AC XY: 56 AN XY: 127366

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.000346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000760

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000455

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000214 AC: 310 AN: 1446252 Hom.: 1 Cov.: 30 AF XY: 0.000188 AC XY: 135 AN XY: 719360

Gnomad4 AFR exome AF: 0.00762

Gnomad4 AMR exome AF: 0.000409

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000486

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.000619

GnomAD4 genome AF: 0.00220 AC: 334 AN: 152126 Hom.: 1 Cov.: 31 AF XY: 0.00194 AC XY: 144 AN XY: 74350

Gnomad4 AFR AF: 0.00776

Gnomad4 AMR AF: 0.000656

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: 0.000473

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.00255

ESP6500AA AF: 0.00976 AC: 43

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000725 AC: 88

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MVP		0.98
MPC		0.89
ClinPred		0.16	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.88

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: rs140507297; hg19: chr20-35675502;