rs201020747

Variant names:

• chr13-48381238-C-T
• rs201020747
• NM_000321.3:c.1499-9C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-48381238-C-T
• chr13-48381238-C-A
• chr13-48381238-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_000321.3(RB1):​c.1499-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 intron
• Scores: Splicing: ADA: 0.0009395
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.242
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 13-48381238-C-T is Benign according to our data. Variant chr13-48381238-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 458128.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1499-9C>T		intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1499-9C>T		intron	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1499-9C>T		intron	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1499-9C>T		intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*867-9C>T		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.1622-9C>T		intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.0000872 AC: 13 AN: 149138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000729

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000744

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00251 AC: 525 AN: 209028 AF XY: 0.00236

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00359

Gnomad EAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00234

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00320

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000412 AC: 585 AN: 1421168 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 284 AN XY: 705586

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

African (AFR) AF: 0.00167 AC: 52 AN: 31050

American (AMR) AF: 0.00275 AC: 103 AN: 37460

Ashkenazi Jewish (ASJ) AF: 0.00133 AC: 33 AN: 24792

East Asian (EAS) AF: 0.000180 AC: 7 AN: 38892

South Asian (SAS) AF: 0.000658 AC: 52 AN: 79000

European-Finnish (FIN) AF: 0.0000957 AC: 5 AN: 52228

Middle Eastern (MID) AF: 0.00104 AC: 5 AN: 4796

European-Non Finnish (NFE) AF: 0.000251 AC: 275 AN: 1094616

Other (OTH) AF: 0.000909 AC: 53 AN: 58334

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000871 AC: 13 AN: 149254 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 4 AN XY: 72728

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

African (AFR) AF: 0.0000245 AC: 1 AN: 40758

American (AMR) AF: 0.00 AC: 0 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.000729 AC: 7 AN: 9602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000745 AC: 5 AN: 67156

Other (OTH) AF: 0.00 AC: 0 AN: 2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00421 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.54
PhyloP100		0.24
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00094
dbscSNV1_RF	Benign	0.096
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: rs201020747; hg19: chr13-48955374; COSMIC: COSV105078135; COSMIC: COSV105078135;