13-48476876-C-T

Variant names:

• chr13-48476876-C-T
• rs3020646
• NM_000321.3:c.2663+33C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000321.3(RB1):​c.2663+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,609,814 control chromosomes in the GnomAD database, including 759,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63708 hom., cov: 32)
  • Exomes 𝑓: 0.98 (696186 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.309
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-48476876-C-T is Benign according to our data. Variant chr13-48476876-C-T is described in ClinVar as Benign. ClinVar VariationId is 255823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.2663+33C>T		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.2663+33C>T		intron	N/A	NP_001394094.1
	RB1	NM_001407168.1		c.113+33C>T		intron	N/A	NP_001394097.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2663+33C>T		intron	N/A	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*2031+33C>T		intron	N/A	ENSP00000434702.1
	RB1	ENST00000484879.1	TSL:1	n.397+33C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.908 AC: 138080 AN: 152124 Hom.: 63670 Cov.: 32

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.932

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.926

GnomAD2 exomes AF: 0.958 AC: 240487 AN: 250916 AF XY: 0.963

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.950

Gnomad ASJ exome AF: 0.932

Gnomad EAS exome AF: 0.997

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.985

Gnomad OTH exome AF: 0.963

GnomAD4 exome AF: 0.976 AC: 1423086 AN: 1457572 Hom.: 696186 Cov.: 38 AF XY: 0.976 AC XY: 708124 AN XY: 725364

African (AFR) AF: 0.715 AC: 23853 AN: 33378

American (AMR) AF: 0.949 AC: 42394 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 24349 AN: 26072

East Asian (EAS) AF: 0.998 AC: 39586 AN: 39652

South Asian (SAS) AF: 0.957 AC: 82276 AN: 86004

European-Finnish (FIN) AF: 0.998 AC: 53065 AN: 53176

Middle Eastern (MID) AF: 0.926 AC: 5335 AN: 5764

European-Non Finnish (NFE) AF: 0.987 AC: 1094369 AN: 1108628

Other (OTH) AF: 0.960 AC: 57859 AN: 60244

GnomAD4 genome AF: 0.908 AC: 138177 AN: 152242 Hom.: 63708 Cov.: 32 AF XY: 0.911 AC XY: 67836 AN XY: 74446

African (AFR) AF: 0.726 AC: 30134 AN: 41488

American (AMR) AF: 0.932 AC: 14257 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3255 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5172 AN: 5188

South Asian (SAS) AF: 0.956 AC: 4610 AN: 4822

European-Finnish (FIN) AF: 0.999 AC: 10613 AN: 10626

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 66993 AN: 68032

Other (OTH) AF: 0.926 AC: 1958 AN: 2114

Alfa AF: 0.954 Hom.: 191478

Bravo AF: 0.896

Asia WGS AF: 0.957 AC: 3330 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.2
DANN	Benign	0.46
PhyloP100		0.31
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: rs3020646; hg19: chr13-49051012;