Genetic Variant RB1:p.Ala18Ser (chr13-48303964-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000321.3(RB1):c.52G>T(p.Ala18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,509,556 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 1 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.48

Publications

13 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011229664).

BP6

Variant 13-48303964-G-T is Benign according to our data. Variant chr13-48303964-G-T is described in ClinVar as Benign. ClinVar VariationId is 237674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000711 (108/151934) while in subpopulation AFR AF = 0.00256 (106/41364). AF 95% confidence interval is 0.00217. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 108 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
RB1	NM_000321.3	MANE Select	c.52G>T	p.Ala18Ser	missense	Exon 1 of 27	NP_000312.2
RB1	NM_001407165.1		c.52G>T	p.Ala18Ser	missense	Exon 1 of 27	NP_001394094.1
RB1	NM_001407166.1		c.52G>T	p.Ala18Ser	missense	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RB1	ENST00000267163.6	TSL:1 MANE Select	c.52G>T	p.Ala18Ser	missense	Exon 1 of 27	ENSP00000267163.4
RB1	ENST00000467505.6	TSL:1	n.52G>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
RB1	ENST00000924352.1		c.52G>T	p.Ala18Ser	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes

AF:

0.000711

AC:

108

AN:

151826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00257

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000663

AC:

AN:

105654

AF XY:

0.0000679

show subpopulations

Gnomad AFR exome

AF:

0.00379

Gnomad AMR exome

AF:

0.00

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:

0.0000759

AC:

103

AN:

1357622

Hom.:

Cov.:

AF XY:

0.0000687

AC XY:

AN XY:

669730

show subpopulations

African (AFR)

AF:

0.00324

AC:

AN:

27790

American (AMR)

AF:

0.0000900

AC:

AN:

33330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24200

East Asian (EAS)

AF:

0.00

AC:

AN:

32536

South Asian (SAS)

AF:

0.00

AC:

AN:

76678

European-Finnish (FIN)

AF:

0.0000294

AC:

AN:

33958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068540

Other (OTH)

AF:

0.000141

AC:

AN:

56558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000711

AC:

108

AN:

151934

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.00256

AC:

106

AN:

41364

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67944

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000854

Hom.:

Bravo

AF:

0.000831

ExAC

AF:

0.0000665

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

Retinoblastoma (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.28

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.55

PhyloP100

1.5

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.12

REVEL

Benign

0.14

Sift

Benign

0.74

Sift4G

Benign

0.77

Polyphen

0.042

Vest4

0.099

MutPred

0.34

Gain of catalytic residue at P23 (P = 5e-04)

MVP

0.72

MPC

0.40

ClinPred

0.055

GERP RS

3.0

PromoterAI

0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.043

gMVP

0.13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over