rs745822791

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6_Very_StrongBS2_Supporting

The ENST00000267163.6(RB1):​c.106G>A​(p.Asp36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,472,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D36G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

RB1
ENST00000267163.6 missense

Scores

2
5
12

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.28
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 Benign. Variant got -9 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in ENST00000267163.6
BP4
Computational evidence support a benign effect (MetaRNN=0.2178818).
BP6
Variant 13-48304018-G-A is Benign according to our data. Variant chr13-48304018-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RB1NM_000321.3 linkuse as main transcriptc.106G>A p.Asp36Asn missense_variant 1/27 ENST00000267163.6 NP_000312.2
RB1NM_001407165.1 linkuse as main transcriptc.106G>A p.Asp36Asn missense_variant 1/27 NP_001394094.1
RB1NM_001407166.1 linkuse as main transcriptc.106G>A p.Asp36Asn missense_variant 1/17 NP_001394095.1
RB1NM_001407167.1 linkuse as main transcriptc.106G>A p.Asp36Asn missense_variant 1/3 NP_001394096.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.106G>A p.Asp36Asn missense_variant 1/271 NM_000321.3 ENSP00000267163 P1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000920
AC:
7
AN:
76124
Hom.:
0
AF XY:
0.0000908
AC XY:
4
AN XY:
44042
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000147
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000642
Gnomad NFE exome
AF:
0.0000691
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000424
AC:
56
AN:
1319918
Hom.:
0
Cov.:
31
AF XY:
0.0000430
AC XY:
28
AN XY:
650728
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000400
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000273
Gnomad4 NFE exome
AF:
0.0000428
Gnomad4 OTH exome
AF:
0.0000183
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152132
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.0000158
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinoblastoma Benign:2
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJul 29, 2024- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 13, 2020This 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
0.084
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
T;.;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.70
T;T;T
M_CAP
Pathogenic
0.70
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Uncertain
0.37
D
MutationAssessor
Benign
0.69
N;.;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.21
N;.;.
REVEL
Benign
0.28
Sift
Benign
0.19
T;.;.
Sift4G
Benign
0.39
T;.;.
Polyphen
0.99
D;.;.
Vest4
0.14
MutPred
0.19
Gain of catalytic residue at G38 (P = 0.1076);Gain of catalytic residue at G38 (P = 0.1076);Gain of catalytic residue at G38 (P = 0.1076);
MVP
0.88
MPC
0.51
ClinPred
0.23
T
GERP RS
3.8
Varity_R
0.19
gMVP
0.19

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.

Other links and lift over

dbSNP: rs745822791; hg19: chr13-48878154; COSMIC: COSV99031811; COSMIC: COSV99031811; API