13-48456226-C-G

Variant names:

• chr13-48456226-C-G
• NM_000321.3:c.1837C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000321.3(RB1):​c.1837C>G​(p.Pro613Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36330768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1837C>G	p.Pro613Ala	missense_variant	Exon 19 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1837C>G	p.Pro613Ala	missense_variant	Exon 19 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1837C>G	p.Pro613Ala	missense_variant	Exon 19 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1837C>G	p.Pro613Ala	missense_variant	Exon 19 of 27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+74783C>G		intron_variant	Intron 1 of 1			ENSP00000496005.1
RB1	ENST00000480491.1	n.536C>G		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P613A variant (also known as c.1837C>G), located in coding exon 19 of the RB1 gene, results from a C to G substitution at nucleotide position 1837. The proline at codon 613 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. 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	0.084
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.42	T;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.058	T;.
Polyphen		0.070	B;.
Vest4		0.52
MutPred		0.39		Loss of glycosylation at P613 (P = 0.0044);Loss of glycosylation at P613 (P = 0.0044);
MVP		0.94
MPC		1.0
ClinPred		0.55	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-49030362;