13-48349023-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000321.3(RB1):c.607G>C(p.Gly203Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G203E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.607G>C	p.Gly203Arg	missense_variant, splice_region_variant	6/27	ENST00000267163.6
RB1	NM_001407165.1	c.607G>C	p.Gly203Arg	missense_variant, splice_region_variant	6/27
RB1	NM_001407166.1	c.607G>C	p.Gly203Arg	missense_variant, splice_region_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.607G>C	p.Gly203Arg	missense_variant, splice_region_variant	6/27	1	NM_000321.3	P1
RB1	ENST00000467505.5	c.138-10994G>C		intron_variant, NMD_transcript_variant		1
RB1	ENST00000650461.1	c.607G>C	p.Gly203Arg	missense_variant, splice_region_variant	6/27
RB1	ENST00000525036.1	n.769G>C		splice_region_variant, non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mendelics

Jul 02, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.48		Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);
MVP		0.92
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
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: rs1012377281; hg19: chr13-48923159;