13-48473795-G-A

Variant names:

• chr13-48473795-G-A
• rs4151611
• NM_000321.3:c.2520+405G>A

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+405G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.053 in 152,026 control chromosomes in the GnomAD database, including 388 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 0.053 (388 hom., cov: 31)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.760
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.2520+405G>A		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.2520+405G>A		intron	N/A	NP_001394094.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2520+405G>A		intron	N/A	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*1888+405G>A		intron	N/A	ENSP00000434702.1
	RB1	ENST00000650461.1		c.2520+405G>A		intron	N/A	ENSP00000497193.1

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8045 AN: 151908 Hom.: 386 Cov.: 31

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0458

Gnomad OTH AF: 0.0378

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

GnomAD4 genome AF: 0.0530 AC: 8050 AN: 152026 Hom.: 388 Cov.: 31 AF XY: 0.0581 AC XY: 4314 AN XY: 74306

African (AFR) AF: 0.00991 AC: 411 AN: 41480

American (AMR) AF: 0.125 AC: 1912 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3470

East Asian (EAS) AF: 0.159 AC: 823 AN: 5162

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4820

European-Finnish (FIN) AF: 0.132 AC: 1393 AN: 10546

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0458 AC: 3116 AN: 67980

Other (OTH) AF: 0.0374 AC: 79 AN: 2110

Alfa AF: 0.0198 Hom.: 8

Bravo AF: 0.0557

Asia WGS AF: 0.0810 AC: 283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.8
DANN	Benign	0.57
PhyloP100		-0.76
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: rs4151611; hg19: chr13-49047931;