rs198584

Variant names:

• chr13-48461331-T-C
• rs198584
• NM_000321.3:c.2106+1498T>C

Variant summary

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

The NM_000321.3(RB1):​c.2106+1498T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,176 control chromosomes in the GnomAD database, including 5,282 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 0.26 (5282 hom., cov: 32)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 9 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=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2106+1498T>C		intron_variant	Intron 20 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2106+1498T>C		intron_variant	Intron 20 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2106+1498T>C		intron_variant	Intron 20 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39760 AN: 152058 Hom.: 5283 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.261 AC: 39771 AN: 152176 Hom.: 5282 Cov.: 32 AF XY: 0.262 AC XY: 19490 AN XY: 74408

African (AFR) AF: 0.299 AC: 12434 AN: 41524

American (AMR) AF: 0.204 AC: 3128 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 724 AN: 3472

East Asian (EAS) AF: 0.228 AC: 1180 AN: 5170

South Asian (SAS) AF: 0.265 AC: 1275 AN: 4820

European-Finnish (FIN) AF: 0.267 AC: 2831 AN: 10592

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17307 AN: 67988

Other (OTH) AF: 0.247 AC: 521 AN: 2108

Alfa AF: 0.265 Hom.: 715

Bravo AF: 0.261

Asia WGS AF: 0.247 AC: 856 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.0
DANN	Benign	0.88
PhyloP100		1.7
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: rs198584; hg19: chr13-49035467;