Variant chr13-48459831-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000321.3(RB1):c.2104C>A(p.Gln702Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q702R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

RB1
NM_000321.3 missense, splice_region

Scores

Splicing: ADA: 0.9090

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.57

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000321.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-48459832-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 428675.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 13-48459831-C-A is Pathogenic according to our data. Variant chr13-48459831-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3237063.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3 linkuse as main transcript	c.2104C>A	p.Gln702Lys	missense_variant, splice_region_variant	20/27	ENST00000267163.6
RB1	NM_001407165.1 linkuse as main transcript	c.2104C>A	p.Gln702Lys	missense_variant, splice_region_variant	20/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RB1	ENST00000267163.6 linkuse as main transcript	c.2104C>A	p.Gln702Lys	missense_variant, splice_region_variant	20/27	1	NM_000321.3	P1
RB1	ENST00000650461.1 linkuse as main transcript	c.2104C>A	p.Gln702Lys	missense_variant, splice_region_variant	20/27
RB1	ENST00000643064.1 linkuse as main transcript	c.194+78388C>A		intron_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

May 20, 2024

Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM1, PM2, PS4SUP, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.99

MutPred

0.85

Gain of catalytic residue at M704 (P = 0);Gain of catalytic residue at M704 (P = 0);

MVP

0.99

MPC

1.5

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.74

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over