rs2854357

Variant names:

• chr13-48375917-T-C
• rs2854357
• NM_000321.3:c.1216-1001T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-48375917-T-C
• chr13-48375917-T-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.1216-1001T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 151,938 control chromosomes in the GnomAD database, including 52,212 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 0.78 (52212 hom., cov: 31)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.174
• Publications: 3 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

LOC112268118 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1216-1001T>C		intron_variant	Intron 12 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1216-1001T>C		intron_variant	Intron 12 of 26		NP_001394094.1
RB1	NM_001407166.1	c.1216-1001T>C		intron_variant	Intron 12 of 16		NP_001394095.1
LOC112268118	XR_002957522.2	n.41-1677A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1216-1001T>C		intron_variant	Intron 12 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.783 AC: 118852 AN: 151816 Hom.: 52219 Cov.: 31

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.816

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

GnomAD4 genome AF: 0.782 AC: 118855 AN: 151938 Hom.: 52212 Cov.: 31 AF XY: 0.788 AC XY: 58524 AN XY: 74312

African (AFR) AF: 0.346 AC: 14310 AN: 41396

American (AMR) AF: 0.878 AC: 13389 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 3192 AN: 3472

East Asian (EAS) AF: 0.868 AC: 4496 AN: 5180

South Asian (SAS) AF: 0.904 AC: 4360 AN: 4822

European-Finnish (FIN) AF: 0.974 AC: 10250 AN: 10520

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 65994 AN: 67994

Other (OTH) AF: 0.810 AC: 1705 AN: 2104

Alfa AF: 0.842 Hom.: 7568

Bravo AF: 0.756

Asia WGS AF: 0.816 AC: 2840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.63
PhyloP100		0.17
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: rs2854357; hg19: chr13-48950053;