chr13-48381523-C-CAA

Variant names:

• chr13-48381523-C-CAA
• rs4151540
• NM_000321.3:c.1695+81_1695+82insAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000321.3(RB1):​c.1695+81_1695+82insAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,281,506 control chromosomes in the GnomAD database, including 45,161 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4251 hom., cov: 24)
  • Exomes 𝑓: 0.26 (40910 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0210
• Publications: 6 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 -10 ACMG points.

• BP6: Variant 13-48381523-C-CAA is Benign according to our data. Variant chr13-48381523-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 1225861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1695+81_1695+82insAA		intron_variant	Intron 17 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407166.1	c.*69_*70insAA		3_prime_UTR_variant	Exon 17 of 17		NP_001394095.1
RB1	NM_001407165.1	c.1695+81_1695+82insAA		intron_variant	Intron 17 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1695+80_1695+81insAA		intron_variant	Intron 17 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35087 AN: 151906 Hom.: 4257 Cov.: 24

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.261 AC: 295159 AN: 1129482 Hom.: 40910 AF XY: 0.261 AC XY: 149955 AN XY: 573572

African (AFR) AF: 0.149 AC: 3896 AN: 26202

American (AMR) AF: 0.271 AC: 10842 AN: 39968

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 4548 AN: 23544

East Asian (EAS) AF: 0.239 AC: 8712 AN: 36426

South Asian (SAS) AF: 0.270 AC: 20453 AN: 75850

European-Finnish (FIN) AF: 0.289 AC: 14961 AN: 51790

Middle Eastern (MID) AF: 0.165 AC: 678 AN: 4112

European-Non Finnish (NFE) AF: 0.266 AC: 218801 AN: 822290

Other (OTH) AF: 0.249 AC: 12268 AN: 49300

GnomAD4 genome AF: 0.231 AC: 35082 AN: 152024 Hom.: 4251 Cov.: 24 AF XY: 0.234 AC XY: 17374 AN XY: 74300

African (AFR) AF: 0.154 AC: 6397 AN: 41502

American (AMR) AF: 0.232 AC: 3546 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 709 AN: 3470

East Asian (EAS) AF: 0.227 AC: 1169 AN: 5146

South Asian (SAS) AF: 0.275 AC: 1326 AN: 4816

European-Finnish (FIN) AF: 0.286 AC: 3028 AN: 10570

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18098 AN: 67932

Other (OTH) AF: 0.214 AC: 452 AN: 2108

Alfa AF: 0.252 Hom.: 516

Bravo AF: 0.225

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.021
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4151540; hg19: chr13-48955659;