rs200658795

chr13-48380042-A-Gchr13-48380042-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000321.3(RB1):c.1390-11A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,198,044 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (7 hom., cov: 30)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: RB1 NM_000321.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007313
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 13-48380042-A-G is Benign according to our data. Variant chr13-48380042-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255821.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=2, Uncertain_significance=1}. Variant chr13-48380042-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00336 (481/143254) while in subpopulation AFR AF= 0.012 (466/38948). AF 95% confidence interval is 0.0111. There are 7 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 483 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1390-11A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.1390-11A>G		splice_polypyrimidine_tract_variant, intron_variant
RB1	NM_001407166.1	c.1390-11A>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1390-11A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000321.3	P1
RB1	ENST00000650461.1	c.1390-11A>G		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 483 AN: 143206 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000910

Gnomad OTH AF: 0.00204

GnomAD3 exomes AF: 0.000596 AC: 68 AN: 114180 Hom.: 1 AF XY: 0.000530 AC XY: 34 AN XY: 64186

Gnomad AFR exome AF: 0.00833

Gnomad AMR exome AF: 0.000481

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000605

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000837

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.000306 AC: 323 AN: 1054790 Hom.: 1 Cov.: 19 AF XY: 0.000256 AC XY: 135 AN XY: 526366

Gnomad4 AFR exome AF: 0.0107

Gnomad4 AMR exome AF: 0.000793

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000335

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000265

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00336 AC: 481 AN: 143254 Hom.: 7 Cov.: 30 AF XY: 0.00318 AC XY: 221 AN XY: 69490

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.000353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000910

Gnomad4 OTH AF: 0.00202

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinoblastoma Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	RB1: BS1, BS2 -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2014

The c.1390-11A>G intronic variant results from an A to G substitution 11 nucleotides upstream from coding exon 15 in the RB1 gene. This variant was previously reported in the SNPDatabase as rs200658795. Based on data from the 1000 Genomes Project, the G allele has an overall frequency of approximately 0.1% (2/2,098) total alleles studied. The highest observed frequency was 0.57% (1/176) Yoruba alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.22% (23/10,564) total alleles studied, having been observed in 0.7% (23/3,288) African American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.29% (greater than 350 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration does not have any significant effect on this splice donor site (http://www.fruitfly.org/seq_tools/splice.html and http://rulai.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi). However, experimental evidence is not available. Since supporting evidence is limited at this time, the clinical significance of c.1390-11A>G remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	15
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200658795; hg19: chr13-48954178;