rs520342

Variant names:

• chr13-48342759-C-A
• rs520342
• NM_000321.3:c.380+45C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-48342759-C-A
• chr13-48342759-C-G
• chr13-48342759-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000321.3(RB1):​c.380+45C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000847 in 1,181,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.380+45C>A		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.380+45C>A		intron	N/A	NP_001394094.1
	RB1	NM_001407166.1		c.380+45C>A		intron	N/A	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.380+45C>A		intron	N/A	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.138-17258C>A		intron	N/A	ENSP00000434702.1
	RB1	ENST00000650461.1		c.380+45C>A		intron	N/A	ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.47e-7 AC: 1 AN: 1181044 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 600116

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27550

American (AMR) AF: 0.00 AC: 0 AN: 42938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24134

East Asian (EAS) AF: 0.00 AC: 0 AN: 38208

South Asian (SAS) AF: 0.00 AC: 0 AN: 78736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5022

European-Non Finnish (NFE) AF: 0.00000116 AC: 1 AN: 861552

Other (OTH) AF: 0.00 AC: 0 AN: 51070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.038
DANN	Benign	0.32
PhyloP100		-2.0

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: rs520342; hg19: chr13-48916895;