13-48464989-C-T

Variant names:

• chr13-48464989-C-T
• rs765386327
• NM_000321.3:c.2212-9C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000321.3(RB1):​c.2212-9C>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 0.23 (0 hom., cov: 0)
  • Exomes 𝑓: 0.086 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 intron
• Scores: Splicing: ADA: 0.00003735
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0290
• 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 13-48464989-C-T is Benign according to our data. Variant chr13-48464989-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416499.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.2212-9C>T		intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.2212-9C>T		intron	N/A	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2212-9C>T		intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*1580-9C>T		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.2335-9C>T		intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 8557 AN: 37692 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0965

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.217

GnomAD2 exomes AF: 0.0508 AC: 8772 AN: 172838 AF XY: 0.0484

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.0858

Gnomad ASJ exome AF: 0.0472

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0822

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0858 AC: 43709 AN: 509204 Hom.: 1 Cov.: 16 AF XY: 0.0897 AC XY: 23964 AN XY: 267280

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

African (AFR) AF: 0.0754 AC: 954 AN: 12658

American (AMR) AF: 0.119 AC: 2647 AN: 22280

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 976 AN: 12046

East Asian (EAS) AF: 0.0852 AC: 1809 AN: 21228

South Asian (SAS) AF: 0.226 AC: 9052 AN: 40066

European-Finnish (FIN) AF: 0.0938 AC: 3104 AN: 33108

Middle Eastern (MID) AF: 0.0887 AC: 143 AN: 1612

European-Non Finnish (NFE) AF: 0.0670 AC: 23041 AN: 344106

Other (OTH) AF: 0.0897 AC: 1983 AN: 22100

⚠️ 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;InbreedingCoeff AF: 0.227 AC: 8557 AN: 37722 Hom.: 0 Cov.: 0 AF XY: 0.205 AC XY: 3775 AN XY: 18388

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

African (AFR) AF: 0.159 AC: 1794 AN: 11270

American (AMR) AF: 0.154 AC: 585 AN: 3810

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 265 AN: 848

East Asian (EAS) AF: 0.202 AC: 258 AN: 1276

South Asian (SAS) AF: 0.168 AC: 193 AN: 1150

European-Finnish (FIN) AF: 0.0965 AC: 173 AN: 1792

Middle Eastern (MID) AF: 0.100 AC: 6 AN: 60

European-Non Finnish (NFE) AF: 0.303 AC: 5077 AN: 16744

Other (OTH) AF: 0.211 AC: 107 AN: 506

⚠️ 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: 0.0484 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	-0.73
CADD	Benign	15
DANN	Benign	0.57
PhyloP100		-0.029
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.026
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs765386327;

hg19: chr13-49039125;