chr13-48307018-G-C

Variant names:

• chr13-48307018-G-C
• rs1981434
• NM_000321.3:c.138-262G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000321.3(RB1):​c.138-262G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 152,074 control chromosomes in the GnomAD database, including 28,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.56 (28469 hom., cov: 33)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0900
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-48307018-G-C is Benign according to our data. Variant chr13-48307018-G-C is described in ClinVar as Benign. ClinVar VariationId is 1244896.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.719 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.138-262G>C		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.138-262G>C		intron	N/A	NP_001394094.1
	RB1	NM_001407166.1		c.138-262G>C		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.138-262G>C		intron	N/A	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.137+2969G>C		intron	N/A	ENSP00000434702.1
	RB1	ENST00000650461.1		c.138-262G>C		intron	N/A	ENSP00000497193.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85755 AN: 151956 Hom.: 28474 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.609

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.564 AC: 85753 AN: 152074 Hom.: 28469 Cov.: 33 AF XY: 0.566 AC XY: 42082 AN XY: 74348

African (AFR) AF: 0.185 AC: 7661 AN: 41438

American (AMR) AF: 0.696 AC: 10648 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2495 AN: 3468

East Asian (EAS) AF: 0.622 AC: 3215 AN: 5170

South Asian (SAS) AF: 0.606 AC: 2928 AN: 4828

European-Finnish (FIN) AF: 0.709 AC: 7492 AN: 10564

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.724 AC: 49231 AN: 67988

Other (OTH) AF: 0.606 AC: 1278 AN: 2110

Alfa AF: 0.499 Hom.: 1666

Bravo AF: 0.547

Asia WGS AF: 0.536 AC: 1864 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.7
DANN	Benign	0.50
PhyloP100		0.090
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: rs1981434; hg19: chr13-48881154;