chr13-48373333-G-A

Position:

• chr13-48373333-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000321.3(RB1):​c.1128-72G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00733 in 931,958 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (44 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.405

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]

LOC112268118 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00556 (846/152188) while in subpopulation NFE AF= 0.00865 (588/67956). AF 95% confidence interval is 0.00807. There are 5 homozygotes in gnomad4. There are 406 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 846 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1128-72G>A		intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1128-72G>A		intron_variant			NP_001394094.1
RB1	NM_001407166.1	c.1128-72G>A		intron_variant			NP_001394095.1
LOC112268118	XR_002957522.2	n.121+827C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1128-72G>A		intron_variant		1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1128-72G>A		intron_variant				ENSP00000497193.1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152070 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00865

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00768 AC: 5987 AN: 779770 Hom.: 44 AF XY: 0.00758 AC XY: 3140 AN XY: 414068

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00594

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00311

Gnomad4 FIN exome AF: 0.00805

Gnomad4 NFE exome AF: 0.00932

Gnomad4 OTH exome AF: 0.00712

GnomAD4 genome AF: 0.00556 AC: 846 AN: 152188 Hom.: 5 Cov.: 31 AF XY: 0.00546 AC XY: 406 AN XY: 74402

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00528

Gnomad4 NFE AF: 0.00865

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00658 Hom.: 3268

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.6
DANN	Benign	0.53

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: rs185587; hg19: chr13-48947469; COSMIC: COSV99922904;