chr13-48347863-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5BP4_ModerateBP6BS2

The NM_000321.3(RB1):​c.539C>T​(p.Ser180Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,582,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S180W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense, splice_region

Scores

2
17
Splicing: ADA: 0.0006400
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.264
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-48347863-C-G is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.07149869).
BP6
Variant 13-48347863-C-T is Benign according to our data. Variant chr13-48347863-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527940.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
BS2
High AC in GnomAdExome4 at 97 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RB1NM_000321.3 linkuse as main transcriptc.539C>T p.Ser180Leu missense_variant, splice_region_variant 5/27 ENST00000267163.6
RB1NM_001407165.1 linkuse as main transcriptc.539C>T p.Ser180Leu missense_variant, splice_region_variant 5/27
RB1NM_001407166.1 linkuse as main transcriptc.539C>T p.Ser180Leu missense_variant, splice_region_variant 5/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.539C>T p.Ser180Leu missense_variant, splice_region_variant 5/271 NM_000321.3 P1
RB1ENST00000467505.5 linkuse as main transcriptc.138-12154C>T intron_variant, NMD_transcript_variant 1
RB1ENST00000650461.1 linkuse as main transcriptc.539C>T p.Ser180Leu missense_variant, splice_region_variant 5/27
RB1ENST00000525036.1 linkuse as main transcriptn.701C>T splice_region_variant, non_coding_transcript_exon_variant 5/73

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151576
Hom.:
0
Cov.:
32
show subpopulations
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:
0.0000295
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000403
AC:
10
AN:
248194
Hom.:
0
AF XY:
0.0000372
AC XY:
5
AN XY:
134314
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000891
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000678
AC:
97
AN:
1430564
Hom.:
0
Cov.:
28
AF XY:
0.0000589
AC XY:
42
AN XY:
713286
show subpopulations
Gnomad4 AFR exome
AF:
0.0000306
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:
0.0000875
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151576
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73982
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:
0.0000295
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000117
AC:
1
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Retinoblastoma Benign:3
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthOct 02, 2023- -
Likely benign, criteria provided, single submitterclinical testingGenetic Diagnostic Laboratory, University of Pennsylvania School of MedicineMay 20, 2024Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:1, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:BP4, BP6 -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
RB1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 20, 2023The RB1 c.539C>T variant is predicted to result in the amino acid substitution p.Ser180Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-48921999-C-T). In ClinVar, this variant is classified as likely benign and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/527940/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2022RB1: BP4 -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 21, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
17
DANN
Benign
0.93
DEOGEN2
Uncertain
0.43
T;.
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.33
N
LIST_S2
Benign
0.59
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.071
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
-0.55
N;.
MutationTaster
Benign
0.81
D
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.7
N;.
REVEL
Benign
0.22
Sift
Benign
0.33
T;.
Sift4G
Benign
0.29
T;.
Polyphen
0.0010
B;.
Vest4
0.058
MVP
0.53
MPC
0.39
ClinPred
0.091
T
GERP RS
-0.78
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.075
gMVP
0.064

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00064
dbscSNV1_RF
Benign
0.10
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.

Other links and lift over

dbSNP: rs367654488; hg19: chr13-48921999; COSMIC: COSV57297256; API