13-48381425-A-T

Position:

• chr13-48381425-A-T

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.1677A>T​(p.Glu559Asp) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.65

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, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1677A>T	p.Glu559Asp	missense_variant	17/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1677A>T	p.Glu559Asp	missense_variant	17/27		NP_001394094.1
RB1	NM_001407166.1	c.1677A>T	p.Glu559Asp	missense_variant	17/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1677A>T	p.Glu559Asp	missense_variant	17/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1677A>T	p.Glu559Asp	missense_variant	17/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.174A>T	p.Glu58Asp	missense_variant	1/2			ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.78		Gain of catalytic residue at L561 (P = 0);Gain of catalytic residue at L561 (P = 0);
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.92
gMVP		0.74

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: rs587778639; hg19: chr13-48955561;