rs1131690843

chr13-48342714-G-Achr13-48342714-G-Cchr13-48342714-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_000321.3(RB1):c.380G>A(p.Ser127Asn) variant causes a missense, splice region change. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S127T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.73

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 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-48342714-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-48342714-G-A is Pathogenic according to our data. Variant chr13-48342714-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428730.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.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	3/27	ENST00000267163.6
RB1	NM_001407165.1	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	3/27
RB1	NM_001407166.1	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	3/27	1	NM_000321.3	P1
RB1	ENST00000467505.5	c.138-17303G>A		intron_variant, NMD_transcript_variant		1
RB1	ENST00000650461.1	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	3/27
RB1	ENST00000525036.1	n.542G>A		splice_region_variant, non_coding_transcript_exon_variant	3/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430450 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 713442

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2020

Not observed in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 15884040, 25928201) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2016

The c.380G>A variant (also known as p.S127N), located in coding exon 3 of the RB1 gene, results from a G to A substitution at nucleotide position 380. The amino acid change results in serine to asparagine at codon 127, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This variant was reported in an individual with bilateral retinoblastoma, but no family history of the disease. The authors also performed RNA studies, which showed aberrant splicing (Nichols KE et al. Hum. Mutat. 2005 Jun; 25(6):566-74). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct experimental evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.069
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.52	N;.
REVEL	Benign	0.10
Sift	Benign	0.34	T;.
Sift4G	Benign	0.93	T;.
Polyphen		0.055	B;.
Vest4		0.31
MutPred		0.70		Loss of ubiquitination at K122 (P = 0.0863);Loss of ubiquitination at K122 (P = 0.0863);
MVP		0.50
MPC		0.43
ClinPred		0.65	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.34
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131690843; hg19: chr13-48916850; COSMIC: COSV57302882; COSMIC: COSV57302882;