13-48453004-A-T

Position:

• chr13-48453004-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000321.3(RB1):​c.1707A>T​(p.Leu569Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L569L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.779

Genes affected

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

RB1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1707A>T	p.Leu569Phe	missense_variant	18/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1707A>T	p.Leu569Phe	missense_variant	18/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1707A>T	p.Leu569Phe	missense_variant	18/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1707A>T	p.Leu569Phe	missense_variant	18/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+71561A>T		intron_variant				ENSP00000496005.1
RB1	ENST00000480491.1	n.406A>T		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460502 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726594

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2019

This sequence change replaces leucine with phenylalanine at codon 569 of the RB1 protein (p.Leu569Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0090	D;.
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.44		Gain of catalytic residue at P568 (P = 0.0337);Gain of catalytic residue at P568 (P = 0.0337);
MVP		0.99
MPC		1.4
ClinPred		0.98	D
GERP RS		0.58
Varity_R		0.90
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3092895; hg19: chr13-49027140;