chr13-48303928-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000321.3(RB1):c.16C>T(p.Pro6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,511,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. P6L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.398

Publications

0 publications found

Variant links:

COSMIC-nc: COSV57323192

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-DT (HGNC:42778): (RB1 divergent transcript)

RB1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16943988).

BP6

Variant 13-48303928-C-T is Benign according to our data. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560. Variant chr13-48303928-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285560.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.16C>T	p.Pro6Ser	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.16C>T	p.Pro6Ser	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000375

AC:

AN:

106590

AF XY:

0.0000168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000185

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000883

AC:

AN:

1359592

Hom.:

Cov.:

AF XY:

0.00000596

AC XY:

AN XY:

670770

show subpopulations

African (AFR)

AF:

0.0000359

AC:

AN:

27888

American (AMR)

AF:

0.000209

AC:

AN:

33512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24274

East Asian (EAS)

AF:

0.00

AC:

AN:

32602

South Asian (SAS)

AF:

0.00

AC:

AN:

76852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1069346

Other (OTH)

AF:

0.0000353

AC:

AN:

56670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.579

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.000458

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 07, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinoblastoma

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jun 07, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.099

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.41

T;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.73

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.59

T;T;T

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.55

N;.;.

PhyloP100

0.40

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.0

N;.;.

REVEL

Benign

0.14

Sift

Benign

0.061

T;.;.

Sift4G

Benign

0.098

T;.;.

Polyphen

0.0

B;.;.

Vest4

0.23

MutPred

0.32

Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);

MVP

0.74

MPC

0.45

ClinPred

0.062

GERP RS

1.1

PromoterAI

0.073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.074

gMVP

0.41

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over