rs587776787

Positions:

• chr13-48463835-G-A
• chr13-48463835-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000321.3(RB1):​c.2211G>A​(p.Glu737=) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.27

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 Likely_pathogenic. Variant got 8 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-48463835-G-A is Pathogenic according to our data. Variant chr13-48463835-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13089.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2211G>A	p.Glu737=	splice_region_variant, synonymous_variant	21/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2211G>A	p.Glu737=	splice_region_variant, synonymous_variant	21/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2211G>A	p.Glu737=	splice_region_variant, synonymous_variant	21/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.2211G>A	p.Glu737=	splice_region_variant, synonymous_variant	21/27			ENSP00000497193
RB1	ENST00000643064.1	c.194+82392G>A		intron_variant				ENSP00000496005

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1997

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2023

The c.2211G>A pathogenic mutation (also known as p.E737E), located in coding exon 21 of the RB1 gene, results from a G to A substitution at nucleotide position 2211. This nucleotide substitution does not change the glutamic acid at codon 737. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in a large kindred affected with retinoblastoma and segregated with disease in at least five affected individuals; however, presented with reduced penetrance in comparison to some typical RB1 pathogenic mutations (Schubert EL et al. Hum Genet, 1997 Oct;100:557-63). In addition, this variant was reported to be the result of a de novo mutation or germline mosaicism in one individual with unilateral retinoblastoma (Fang X et al. Ophthalmic Genet . 2021 Oct;42(5):593-599). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776787; hg19: chr13-49037971; COSMIC: COSV57304262;