NM_000321.3:c.380G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000321.3(RB1):c.380G>A(p.Ser127Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 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

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.73

Publications

8 publications found

Variant links:

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

RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-48342714-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 428730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RB1	NM_000321.3 link	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	Exon 3 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1 link	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	Exon 3 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	Exon 3 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.380G>A	p.Ser127Asn	missense_variant, splice_region_variant	Exon 3 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1430450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713442

African (AFR)

AF:

0.00

AC:

AN:

32784

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00

AC:

AN:

85524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083874

Other (OTH)

AF:

0.00

AC:

AN:

59358

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:1

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Case and Pedigree Information: BILATERAL CASES:2, UNILATERAL CASES:1, TOTAL CASES:3, PEDIGREES:3. ACMG Codes Applied:PVS1, PM2, PS4SUP -

not provided

Pathogenic:1

Mar 02, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 04, 2016

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.069

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.34

N;.

PhyloP100

3.7

PrimateAI

Uncertain

0.51

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

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.34

gMVP

0.37

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over