chr13-48347863-C-A

Variant names:

• chr13-48347863-C-A
• NM_000321.3:c.539C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000321.3(RB1):​c.539C>A​(p.Ser180*) variant causes a stop gained, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0006878
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.264

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.539C>A	p.Ser180*	stop_gained, splice_region_variant	Exon 5 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.539C>A	p.Ser180*	stop_gained, splice_region_variant	Exon 5 of 27		NP_001394094.1
RB1	NM_001407166.1	c.539C>A	p.Ser180*	stop_gained, splice_region_variant	Exon 5 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.539C>A	p.Ser180*	stop_gained, splice_region_variant	Exon 5 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000467505.5	n.138-12154C>A		intron_variant	Intron 1 of 2	1		ENSP00000434702.1
RB1	ENST00000650461.1	c.539C>A	p.Ser180*	stop_gained, splice_region_variant	Exon 5 of 27			ENSP00000497193.1
RB1	ENST00000525036.1	n.701C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430566 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 713286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.42	N
Vest4		0.84
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00069
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48921999; COSMIC: COSV104565328;