13-48373333-G-T

Position:

• chr13-48373333-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.1128-72G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 931,782 control chromosomes in the GnomAD database, including 432,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66027 hom., cov: 31)
  • Exomes 𝑓: 0.97 (366315 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 13-48373333-G-T is Benign according to our data. Variant chr13-48373333-G-T is described in ClinVar as [Benign]. Clinvar id is 1272879.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.1128-72G>T		intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1128-72G>T		intron_variant			NP_001394094.1
RB1	NM_001407166.1	c.1128-72G>T		intron_variant			NP_001394095.1
LOC112268118	XR_002957522.2	n.121+827C>A		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.929 AC: 141218 AN: 152056 Hom.: 65988 Cov.: 31

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.954

Gnomad FIN AF: 0.993

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.976

Gnomad OTH AF: 0.937

GnomAD4 exome AF: 0.969 AC: 755330 AN: 779608 Hom.: 366315 AF XY: 0.969 AC XY: 400961 AN XY: 413994

Gnomad4 AFR exome AF: 0.817

Gnomad4 AMR exome AF: 0.949

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.954

Gnomad4 FIN exome AF: 0.990

Gnomad4 NFE exome AF: 0.977

Gnomad4 OTH exome AF: 0.956

GnomAD4 genome AF: 0.929 AC: 141318 AN: 152174 Hom.: 66027 Cov.: 31 AF XY: 0.931 AC XY: 69240 AN XY: 74396

Gnomad4 AFR AF: 0.817

Gnomad4 AMR AF: 0.937

Gnomad4 ASJ AF: 0.933

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.954

Gnomad4 FIN AF: 0.993

Gnomad4 NFE AF: 0.976

Gnomad4 OTH AF: 0.937

Alfa AF: 0.969 Hom.: 3268

Bravo AF: 0.926

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	-0.79
CADD	Benign	2.1
DANN	Benign	0.55

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: COSV99922902;