Variant chr13-48349024-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000321.3(RB1):c.607+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000693 in 1,442,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RB1
NM_000321.3 splice_donor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-48349024-G-T is Pathogenic according to our data. Variant chr13-48349024-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.607+1G>T	splice_donor_variant, intron_variant	Intron 6 of 26	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.607+1G>T	splice_donor_variant, intron_variant	Intron 6 of 26		NP_001394094.1
RB1	NM_001407166.1 link	c.607+1G>T	splice_donor_variant, intron_variant	Intron 6 of 16		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RB1	ENST00000267163.6 link	c.607+1G>T	splice_donor_variant, intron_variant	Intron 6 of 26	1	NM_000321.3	ENSP00000267163.4	P06400
RB1	ENST00000467505.5 link	n.138-10993G>T	intron_variant	Intron 1 of 2	1		ENSP00000434702.1	Q92728
RB1	ENST00000650461.1 link	c.607+1G>T	splice_donor_variant, intron_variant	Intron 6 of 26			ENSP00000497193.1	A0A3B3IS71
RB1	ENST00000525036.1 link	n.769+1G>T	splice_donor_variant, intron_variant	Intron 6 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442952

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000195

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:5

Mar 14, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RB1 c.607+1G>T intronic change results in a G to T substitution at the +1 position of intron 6 of the RB1 gene. This variant results in skipping of exon 6 resulting in a premature termination codon and nonsense-mediated decay (PMID: 12016586, 18000883). This variant has been identified in individuals with a personal and/or family history of retinoblastoma (PMID: 8651278, 12016586, 17096365, 28575107, internal data) and osteosarcoma (internal data). Interestingly, there are several reported carriers of this variant who did not develop retinoblastoma. It is thought to be associated with differential penetrance based on the sex of the transmitted parent, where paternally inherited alleles show increased penetrance (PMID: 12016586, 17096365). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

Jul 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Case and Pedigree Information: BILATERAL CASES:2, UNILATERAL CASES:4, TOTAL CASES:6, PEDIGREES:6. ACMG Codes Applied:PVS1, PM2, PS4SUP -

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 6 of the RB1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with retinoblastoma (PMID: 8651278, 12016586, 16269091, 17096365, 26925970, 28575107). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13093). Studies have shown that disruption of this splice site results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 18000883). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Aug 24, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to cause skipping of exon 6 and a premature stop codon in exon 7, resulting in a null allele in a gene for which loss-of-function is a known mechanism of disease (Klutz et al., 2002; Gamez-Pozo et al., 2007); Analysis of multiple families showed increased penetrance when c.607+1G>T was paternally inherited (71% compared to 9% when maternally inherited), suggesting this variant is associated with a parent-of-origin effect (Klutz et al., 2002; Taylor et al., 2007; Buiting et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8651278, 24814393, 26925970, 21654082, 25754945, 16269091, 18000883, 14722923, 12541220, 10660960, 11317357, 23820649, 10023315, 25525159, 28575107, 17096365, 20551090, 12016586, 33670346, 34680218) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 11, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.607+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 6 of the RB1 gene. This mutation has been reported in multiple individuals/families with retinoblastoma (Ambry internal data; Lohmann DR et al. Am. J. Hum. Genet. 1996 May;58:940-9; Tomar S et al. PLoS ONE. 2017 Jun;12:e0178776; Taylor M et al. Hum. Mutat. 2007 Mar;28:284-93; Klutz M et al. Am. J. Hum. Genet. 2002 Jul;71:174-9). RNA analyses from affected individuals have shown that this alteration leads to skipping of exon 6 (Ambry internal data; Gámez-Pozo A et al. Hum. Mutat. 2007 Dec;28:1245; Klutz M et al. Am. J. Hum. Genet. 2002 Jul;71:174-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Malignant tumor of urinary bladder;C0035335:Retinoblastoma;C0149925:Small cell lung carcinoma;C0585442:Bone osteosarcoma

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PS4_Supporting+PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.90

GERP RS

4.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over