chr13-48380164-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_000321.3(RB1):​c.1422-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000064 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.92
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.1, offset of -37, new splice context is: aaatttttttctttttatAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP5
Variant 13-48380164-G-T is Pathogenic according to our data. Variant chr13-48380164-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1772274.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RB1NM_000321.3 linkc.1422-1G>T splice_acceptor_variant, intron_variant Intron 15 of 26 ENST00000267163.6 NP_000312.2 P06400A0A024RDV3
RB1NM_001407165.1 linkc.1422-1G>T splice_acceptor_variant, intron_variant Intron 15 of 26 NP_001394094.1
RB1NM_001407166.1 linkc.1422-1G>T splice_acceptor_variant, intron_variant Intron 15 of 16 NP_001394095.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkc.1422-1G>T splice_acceptor_variant, intron_variant Intron 15 of 26 1 NM_000321.3 ENSP00000267163.4 P06400
RB1ENST00000650461.1 linkc.1422-1G>T splice_acceptor_variant, intron_variant Intron 15 of 26 ENSP00000497193.1 A0A3B3IS71

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
1
AN:
144816
Hom.:
0
Cov.:
30
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000150
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000636
AC:
9
AN:
1415680
Hom.:
0
Cov.:
31
AF XY:
0.00000711
AC XY:
5
AN XY:
702904
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000101
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000129
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000184
Gnomad4 OTH exome
AF:
0.0000343
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000691
AC:
1
AN:
144816
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
69966
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000150
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
May 09, 2019
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1422-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 16 of the RB1 gene. This alteration was seen in a one-year-old patient with bilateral retinoblastoma (Ottaviani D et al. Ophthalmic Genet., 2013 Dec;34:189-98). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
33
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.91
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.91
Position offset: 1

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.

Other links and lift over

dbSNP: rs1461382798; hg19: chr13-48954300; COSMIC: COSV99926204; COSMIC: COSV99926204; API