rs399413

Variant names:

• chr13-48374433-A-G
• rs399413
• NM_000321.3:c.1215+941A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-48374433-A-G
• chr13-48374433-A-T

Variant summary

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

The NM_000321.3(RB1):​c.1215+941A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 152,022 control chromosomes in the GnomAD database, including 29,087 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 0.57 (29087 hom., cov: 32)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.623
• Publications: 10 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1215+941A>G		intron_variant	Intron 12 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1215+941A>G		intron_variant	Intron 12 of 26		NP_001394094.1
RB1	NM_001407166.1	c.1215+941A>G		intron_variant	Intron 12 of 16		NP_001394095.1
LOC112268118	XR_002957522.2	n.41-193T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1215+941A>G		intron_variant	Intron 12 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87070 AN: 151902 Hom.: 29091 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.694

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.718

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.729

Gnomad OTH AF: 0.612

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

GnomAD4 genome AF: 0.573 AC: 87074 AN: 152022 Hom.: 29087 Cov.: 32 AF XY: 0.575 AC XY: 42764 AN XY: 74308

African (AFR) AF: 0.201 AC: 8322 AN: 41474

American (AMR) AF: 0.694 AC: 10598 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2497 AN: 3466

East Asian (EAS) AF: 0.640 AC: 3304 AN: 5166

South Asian (SAS) AF: 0.644 AC: 3106 AN: 4824

European-Finnish (FIN) AF: 0.718 AC: 7583 AN: 10556

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49579 AN: 67958

Other (OTH) AF: 0.609 AC: 1285 AN: 2110

Alfa AF: 0.684 Hom.: 18683

Bravo AF: 0.554

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.1
DANN	Benign	0.67
PhyloP100		0.62
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: rs399413; hg19: chr13-48948569;