chr13-48474923-C-G

Variant names:

• chr13-48474923-C-G
• rs4151620
• NM_000321.3:c.2520+1533C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000321.3(RB1):​c.2520+1533C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,040 control chromosomes in the GnomAD database, including 1,027 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1027 hom., cov: 31)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.511
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2520+1533C>G		intron_variant	Intron 24 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2520+1533C>G		intron_variant	Intron 24 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2520+1533C>G		intron_variant	Intron 24 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16489 AN: 151922 Hom.: 1029 Cov.: 31

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0866

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.113

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.108 AC: 16485 AN: 152040 Hom.: 1027 Cov.: 31 AF XY: 0.111 AC XY: 8222 AN XY: 74300

African (AFR) AF: 0.0481 AC: 1996 AN: 41496

American (AMR) AF: 0.167 AC: 2545 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3466

East Asian (EAS) AF: 0.0866 AC: 449 AN: 5184

South Asian (SAS) AF: 0.117 AC: 562 AN: 4806

European-Finnish (FIN) AF: 0.128 AC: 1353 AN: 10550

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8859 AN: 67968

Other (OTH) AF: 0.111 AC: 235 AN: 2108

Alfa AF: 0.115 Hom.: 146

Bravo AF: 0.108

Asia WGS AF: 0.0880 AC: 308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.73
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4151620; hg19: chr13-49049059;