rs4151611

Positions:

• chr13-48473795-G-A
• chr13-48473795-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2520+405G>A		intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2520+405G>A		intron_variant			NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2520+405G>A		intron_variant		1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000643064.1	c.194+92352G>A		intron_variant				ENSP00000496005
RB1	ENST00000650461.1	c.2520+405G>A		intron_variant				ENSP00000497193

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

Gnomad4 AFR AF: 0.00991

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.0458

Gnomad4 OTH AF: 0.0374

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.8
DANN	Benign	0.57

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

LitVar

Other links and lift over

dbSNP: rs4151611; hg19: chr13-49047931;