rs1555295597

Variant names:

• chr13-48480039-A-G
• rs1555295597
• NM_000321.3:c.2755A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-48480039-A-G
• chr13-48480039-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000321.3(RB1):​c.2755A>G​(p.Ser919Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S919N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.63
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07361379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2755A>G	p.Ser919Gly	missense_variant	Exon 27 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407168.1	c.205A>G	p.Ser69Gly	missense_variant	Exon 4 of 4		NP_001394097.1
RB1	NM_001407165.1	c.*2A>G		3_prime_UTR_variant	Exon 27 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2755A>G	p.Ser919Gly	missense_variant	Exon 27 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:2

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with glycine at codon 919 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RB1-related disease. This sequence change replaces serine with glycine at codon 919 of the RB1 protein (p.Ser919Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 13, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S919G variant (also known as c.2755A>G), located in coding exon 27 of the RB1 gene, results from an A to G substitution at nucleotide position 2755. The serine at codon 919 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.72
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N
PhyloP100		3.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.18
Sift	Benign	0.43	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.33		Loss of phosphorylation at S919 (P = 0.0106);
MVP		0.67
MPC		0.41
ClinPred		0.14	T
GERP RS		3.7
Varity_R		0.083
gMVP		0.033
Mutation Taster		=94/6	polymorphism

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: rs1555295597; hg19: chr13-49054175;