dbSNP rs758187955: RB1:p.Asn405Lys (chr13-48373492-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000321.3(RB1):c.1215C>A(p.Asn405Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N405N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 missense, splice_region

Scores

Splicing: ADA: 0.00004084

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.44

Publications

0 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 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 links:

LOC112268118 (HGNC:):

LOC112268118 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 27 uncertain in NM_000321.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1584132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RB1	NM_000321.3 link	c.1215C>A	p.Asn405Lys	missense_variant, splice_region_variant	Exon 12 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1 link	c.1215C>A	p.Asn405Lys	missense_variant, splice_region_variant	Exon 12 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.1215C>A	p.Asn405Lys	missense_variant, splice_region_variant	Exon 12 of 17		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.121+668G>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.1215C>A	p.Asn405Lys	missense_variant, splice_region_variant	Exon 12 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1388208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694298

African (AFR)

AF:

0.00

AC:

AN:

31812

American (AMR)

AF:

0.00

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25684

East Asian (EAS)

AF:

0.00

AC:

AN:

39100

South Asian (SAS)

AF:

0.00

AC:

AN:

84544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045632

Other (OTH)

AF:

0.00

AC:

AN:

57938

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.4

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.90

L;.

PhyloP100

2.4

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.59

N;.

REVEL

Benign

0.24

Sift

Benign

0.59

T;.

Sift4G

Benign

0.84

T;.

Polyphen

0.0090

B;.

Vest4

0.39

MutPred

0.52

Gain of catalytic residue at V409 (P = 0.0016);Gain of catalytic residue at V409 (P = 0.0016);

MVP

0.53

MPC

0.76

ClinPred

0.58

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.20

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000041

dbscSNV1_RF

Benign

0.014

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over