Genetic Variant NM_000321.3:c.13A>G (chr13-48303925-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000321.3(RB1):c.13A>G(p.Thr5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000519 in 1,347,594 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T5S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.376

Publications

7 publications found

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:

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08283746).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RB1	NM_000321.3	MANE Select	c.13A>G	p.Thr5Ala	missense	Exon 1 of 27	NP_000312.2	P06400
RB1	NM_001407165.1		c.13A>G	p.Thr5Ala	missense	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
RB1	NM_001407166.1		c.13A>G	p.Thr5Ala	missense	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.13A>G	p.Thr5Ala	missense	Exon 1 of 27	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.13A>G		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
RB1	ENST00000924352.1		c.13A>G	p.Thr5Ala	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000519

AC:

AN:

1347594

Hom.:

Cov.:

AF XY:

0.00000601

AC XY:

AN XY:

665150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27422

American (AMR)

AF:

0.00

AC:

AN:

33014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23648

East Asian (EAS)

AF:

0.00

AC:

AN:

31552

South Asian (SAS)

AF:

0.00

AC:

AN:

76610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3928

European-Non Finnish (NFE)

AF:

0.00000659

AC:

AN:

1062176

Other (OTH)

AF:

0.00

AC:

AN:

55862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.31

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.29

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.69

MutationAssessor

Benign

-0.34

PhyloP100

0.38

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.24

REVEL

Benign

0.20

Sift

Benign

0.41

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.067

MutPred

0.34

Gain of catalytic residue at P2 (P = 0)

MVP

0.62

MPC

0.43

ClinPred

0.093

GERP RS

-3.0

PromoterAI

-0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.10

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over