rs4151448

Variant names:

• chr13-48343537-A-G
• rs4151448
• NM_000321.3:c.380+823A>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.380+823A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,190 control chromosomes in the GnomAD database, including 2,444 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 (2444 hom., cov: 32)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.380+823A>G		intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.380+823A>G		intron	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.380+823A>G		intron	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.380+823A>G		intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.138-16480A>G		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.380+823A>G		intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16068 AN: 152072 Hom.: 2417 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0490

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00543

Gnomad OTH AF: 0.0957

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

GnomAD4 genome AF: 0.106 AC: 16152 AN: 152190 Hom.: 2444 Cov.: 32 AF XY: 0.105 AC XY: 7784 AN XY: 74428

African (AFR) AF: 0.330 AC: 13690 AN: 41448

American (AMR) AF: 0.0453 AC: 694 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.131 AC: 679 AN: 5186

South Asian (SAS) AF: 0.0490 AC: 237 AN: 4832

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00541 AC: 368 AN: 68008

Other (OTH) AF: 0.102 AC: 215 AN: 2112

Alfa AF: 0.0346 Hom.: 975

Bravo AF: 0.119

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.3
DANN	Benign	0.82
PhyloP100		1.2
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: rs4151448; hg19: chr13-48917673;