NM_000321.3:c.1472T>C

Variant names:

• chr13-48380215-T-C
• rs587778848
• NM_000321.3:c.1472T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000321.3(RB1):​c.1472T>C​(p.Leu491Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.14

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1472T>C	p.Leu491Pro	missense_variant	Exon 16 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1472T>C	p.Leu491Pro	missense_variant	Exon 16 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1472T>C	p.Leu491Pro	missense_variant	Exon 16 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1472T>C	p.Leu491Pro	missense_variant	Exon 16 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1472T>C	p.Leu491Pro	missense_variant	Exon 16 of 27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM1, PM2 -

not provided Uncertain:1

Apr 06, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.76		Gain of catalytic residue at L486 (P = 0.0044);Gain of catalytic residue at L486 (P = 0.0044);
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs587778848; hg19: chr13-48954351; COSMIC: COSV57323117; COSMIC: COSV57323117;