rs3092881

Variant names:

• chr13-48342726-T-C
• rs3092881
• NM_000321.3:c.380+12T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-48342726-T-C
• chr13-48342726-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000267163.6(RB1):​c.380+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,533,144 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (16 hom.)
• Consequence: RB1 ENST00000267163.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.955
• Publications: 1 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=-0.72).
• BP6: Variant 13-48342726-T-C is Benign according to our data. Variant chr13-48342726-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00998 (1519/152164) while in subpopulation AFR AF = 0.0347 (1441/41548). AF 95% confidence interval is 0.0332. There are 35 homozygotes in GnomAd4. There are 747 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1519 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000267163.6. 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+12T>C		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.380+12T>C		intron	N/A	NP_001394094.1
	RB1	NM_001407166.1		c.380+12T>C		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+12T>C		intron	N/A	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.138-17291T>C		intron	N/A	ENSP00000434702.1
	RB1	ENST00000650461.1		c.380+12T>C		intron	N/A	ENSP00000497193.1

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1515 AN: 152046 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00264 AC: 659 AN: 249928 AF XY: 0.00180

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000999 AC: 1379 AN: 1380980 Hom.: 16 Cov.: 24 AF XY: 0.000862 AC XY: 596 AN XY: 691524

African (AFR) AF: 0.0344 AC: 1092 AN: 31754

American (AMR) AF: 0.00198 AC: 88 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39168

South Asian (SAS) AF: 0.000142 AC: 12 AN: 84490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53128

Middle Eastern (MID) AF: 0.000894 AC: 5 AN: 5592

European-Non Finnish (NFE) AF: 0.0000558 AC: 58 AN: 1039026

Other (OTH) AF: 0.00215 AC: 124 AN: 57650

GnomAD4 genome AF: 0.00998 AC: 1519 AN: 152164 Hom.: 35 Cov.: 32 AF XY: 0.0100 AC XY: 747 AN XY: 74400

African (AFR) AF: 0.0347 AC: 1441 AN: 41548

American (AMR) AF: 0.00360 AC: 55 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67910

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00678 Hom.: 9

Bravo AF: 0.0115

Asia WGS AF: 0.000868 AC: 3 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Retinoblastoma (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism

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: rs3092881; hg19: chr13-48916862; COSMIC: COSV104565322;