rs896487590

chr13-48304021-A-Cchr13-48304021-A-Gchr13-48304021-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000321.3(RB1):c.109A>C(p.Ser37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,315,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S37G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.85

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20280349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.109A>C	p.Ser37Arg	missense_variant	1/27	ENST00000267163.6
RB1	NM_001407165.1	c.109A>C	p.Ser37Arg	missense_variant	1/27
RB1	NM_001407166.1	c.109A>C	p.Ser37Arg	missense_variant	1/17
RB1	NM_001407167.1	c.109A>C	p.Ser37Arg	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.109A>C	p.Ser37Arg	missense_variant	1/27	1	NM_000321.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1315728 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 648602

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: 9.52e-7

Gnomad4 OTH exome AF: 0.0000183

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 527902). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 37 of the RB1 protein (p.Ser37Arg). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2020

The p.S37R variant (also known as c.109A>C), located in coding exon 1 of the RB1 gene, results from an A to C substitution at nucleotide position 109. The serine at codon 37 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.21
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-0.061
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	0.068	D
MutationAssessor	Benign	0.97	L;.;.
MutationTaster	Benign	0.63	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.18	N;.;.
REVEL	Benign	0.19
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.12	T;.;.
Polyphen		0.84	P;.;.
Vest4		0.26
MutPred		0.25		Loss of glycosylation at S37 (P = 0.0043);Loss of glycosylation at S37 (P = 0.0043);Loss of glycosylation at S37 (P = 0.0043);
MVP		0.81
MPC		0.53
ClinPred		0.56	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.19
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs896487590; hg19: chr13-48878157;