rs768305224

Positions:

• chr13-48360053-C-A
• chr13-48360053-C-G
• chr13-48360053-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.644C>A​(p.Ser215Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.68

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48360053-C-A is Pathogenic according to our data. Variant chr13-48360053-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 428743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48360053-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.644C>A	p.Ser215Ter	stop_gained	7/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.644C>A	p.Ser215Ter	stop_gained	7/27		NP_001394094.1
RB1	NM_001407166.1	c.644C>A	p.Ser215Ter	stop_gained	7/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.644C>A	p.Ser215Ter	stop_gained	7/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000467505.5	c.*12C>A		3_prime_UTR_variant, NMD_transcript_variant	2/3	1		ENSP00000434702
RB1	ENST00000650461.1	c.644C>A	p.Ser215Ter	stop_gained	7/27			ENSP00000497193
RB1	ENST00000525036.1	n.806C>A		non_coding_transcript_exon_variant	7/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2018

This variant has been observed in individuals affected with retinoblastoma (PMID: 12173465, 12541220, 15884040) and has also been reported to be de novo in an individual with bilateral retinoblastoma (PMID: 28193182). This variant is also known as g.56889C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 428743). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser215*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2014

The p.S215* pathogenic mutation (also known as c.644C>A) located in coding exon 7 of the RB1 gene, results from a C to A substitution at nucleotide position 644. This changes the amino acid from a serine to a stop codon within coding exon 7. This mutation has been identified in multiple individuals affected with hereditary retinoblastoma (Nichols KE et al. Hum. Mutat. 2005; 25:566-74, Richter S et al. Am. J. Hum. Genet. 2003; 72:253-69). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A
Vest4		0.96
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs768305224; hg19: chr13-48934189; COSMIC: COSV57294725;