chr13-48373333-G-T

Variant names:

• chr13-48373333-G-T
• rs185587
• NM_000321.3:c.1128-72G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.1128-72G>T		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.1128-72G>T		intron	N/A	NP_001394094.1
	RB1	NM_001407166.1		c.1128-72G>T		intron	N/A	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1128-72G>T		intron	N/A	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*496-72G>T		intron	N/A	ENSP00000434702.1
	RB1	ENST00000650461.1		c.1128-72G>T		intron	N/A	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

African (AFR) AF: 0.817 AC: 16356 AN: 20030

American (AMR) AF: 0.949 AC: 39788 AN: 41914

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 20009 AN: 21534

East Asian (EAS) AF: 0.999 AC: 35976 AN: 36024

South Asian (SAS) AF: 0.954 AC: 65856 AN: 68998

European-Finnish (FIN) AF: 0.990 AC: 51795 AN: 52322

Middle Eastern (MID) AF: 0.913 AC: 3528 AN: 3866

European-Non Finnish (NFE) AF: 0.977 AC: 485928 AN: 497182

Other (OTH) AF: 0.956 AC: 36094 AN: 37738

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

African (AFR) AF: 0.817 AC: 33926 AN: 41520

American (AMR) AF: 0.937 AC: 14339 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 3239 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5166 AN: 5184

South Asian (SAS) AF: 0.954 AC: 4604 AN: 4826

European-Finnish (FIN) AF: 0.993 AC: 10531 AN: 10600

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.976 AC: 66354 AN: 67954

Other (OTH) AF: 0.937 AC: 1981 AN: 2114

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

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.55
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs185587; hg19: chr13-48947469;