rs1340503453

chr13-48348947-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_000321.3(RB1):c.540-9G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,438,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RB1 NM_000321.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002723
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.667

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 Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 13-48348947-G-C is Benign according to our data. Variant chr13-48348947-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 458172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.540-9G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.540-9G>C		splice_polypyrimidine_tract_variant, intron_variant
RB1	NM_001407166.1	c.540-9G>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.540-9G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000321.3	P1
RB1	ENST00000467505.5	c.138-11070G>C		intron_variant, NMD_transcript_variant		1
RB1	ENST00000650461.1	c.540-9G>C		splice_polypyrimidine_tract_variant, intron_variant
RB1	ENST00000525036.1	n.702-9G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244746 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132688

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1438640 Hom.: 0 Cov.: 30 AF XY: 0.00000559 AC XY: 4 AN XY: 715466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	14
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.16
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

Publications

LitVar

Other links and lift over

dbSNP: rs1340503453; hg19: chr13-48923083;