rs198580

Positions:

• chr13-48459611-G-A
• chr13-48459611-G-C
• chr13-48459611-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000321.3(RB1):​c.1961-77G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.958 in 1,449,372 control chromosomes in the GnomAD database, including 668,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61471 hom., cov: 32)
  • Exomes 𝑓: 0.97 (607254 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.292

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-48459611-G-A is Benign according to our data. Variant chr13-48459611-G-A is described in ClinVar as [Benign]. Clinvar id is 1222742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1961-77G>A		intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1961-77G>A		intron_variant			NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1961-77G>A		intron_variant		1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1961-77G>A		intron_variant				ENSP00000497193.1
RB1	ENST00000643064.1	c.192+78168G>A		intron_variant				ENSP00000496005.1

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135268 AN: 152068 Hom.: 61450 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.917

Gnomad NFE AF: 0.976

Gnomad OTH AF: 0.908

GnomAD4 exome AF: 0.966 AC: 1253427 AN: 1297186 Hom.: 607254 AF XY: 0.966 AC XY: 631970 AN XY: 653924

Gnomad4 AFR exome AF: 0.670

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.953

Gnomad4 FIN exome AF: 0.990

Gnomad4 NFE exome AF: 0.978

Gnomad4 OTH exome AF: 0.949

GnomAD4 genome AF: 0.889 AC: 135347 AN: 152186 Hom.: 61471 Cov.: 32 AF XY: 0.893 AC XY: 66468 AN XY: 74414

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.920

Gnomad4 ASJ AF: 0.933

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.953

Gnomad4 FIN AF: 0.994

Gnomad4 NFE AF: 0.976

Gnomad4 OTH AF: 0.909

Alfa AF: 0.918 Hom.: 2504

Bravo AF: 0.875

Asia WGS AF: 0.947 AC: 3296 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs198580; hg19: chr13-49033747;