chr13-48465318-T-G

Variant names:

• chr13-48465318-T-G
• rs774744607
• NM_000321.3:c.2439T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000321.3(RB1):​c.2439T>G​(p.Tyr813*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 28)
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.40
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 13-48465318-T-G is Pathogenic according to our data. Variant chr13-48465318-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 428718.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.2439T>G	p.Tyr813*	stop_gained	Exon 23 of 27	NP_000312.2
	RB1	NM_001407165.1		c.2439T>G	p.Tyr813*	stop_gained	Exon 23 of 27	NP_001394094.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2439T>G	p.Tyr813*	stop_gained	Exon 23 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*1807T>G		non_coding_transcript_exon	Exon 18 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*1807T>G		3_prime_UTR	Exon 18 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 12, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y813* pathogenic mutation (also known as c.2439T>G), located in coding exon 23 of the RB1 gene, results from a T to G substitution at nucleotide position 2439. This changes the amino acid from a tyrosine to a stop codon within coding exon 23. This alteration was previously detected inone family ina cohort of individuals withbilateral or unilateralfamilialretinoblastoma(Richter S et al.Am. J. Hum. Genet.2003;72(2):253-69). In addition to the clinical information presented in the literature, since premature stop codons 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).<br />

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		1.4
Vest4		0.97
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs774744607; hg19: chr13-49039454;