Variant 13-48456251-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_000321.3(RB1):c.1862G>T(p.Arg621Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R621C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

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:

RB1 (HGNC:):

RB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-48456250-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.28905755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3 linkuse as main transcript	c.1862G>T	p.Arg621Leu	missense_variant	19/27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 linkuse as main transcript	c.1862G>T	p.Arg621Leu	missense_variant	19/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RB1	ENST00000267163.6 linkuse as main transcript	c.1862G>T	p.Arg621Leu	missense_variant	19/27	1	NM_000321.3	ENSP00000267163.4	P06400
RB1	ENST00000650461.1 linkuse as main transcript	c.1862G>T	p.Arg621Leu	missense_variant	19/27			ENSP00000497193.1	A0A3B3IS71
RB1	ENST00000643064.1 linkuse as main transcript	c.192+74808G>T		intron_variant				ENSP00000496005.1	A0A2R8Y743
RB1	ENST00000480491.1 linkuse as main transcript	n.561G>T		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

0.081

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.29

T;T

MetaSVM

Uncertain

0.089

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.26

Sift

Benign

0.17

T;.

Sift4G

Benign

0.26

T;.

Polyphen

0.36

B;.

Vest4

0.24

MutPred

0.34

Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);

MVP

0.84

MPC

0.56

ClinPred

0.76

GERP RS

5.1

Varity_R

0.074

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over