rs1555286676

Variant names:

• chr13-48381239-A-G
• rs1555286676
• NM_000321.3:c.1499-8A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-48381239-A-G
• chr13-48381239-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000321.3(RB1):​c.1499-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,582,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RB1 NM_000321.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009014
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0120
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 13-48381239-A-G is Benign according to our data. Variant chr13-48381239-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1133785.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1499-8A>G		splice_region_variant, intron_variant	Intron 16 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1499-8A>G		splice_region_variant, intron_variant	Intron 16 of 26		NP_001394094.1
RB1	NM_001407166.1	c.1499-8A>G		splice_region_variant, intron_variant	Intron 16 of 16		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1499-8A>G		splice_region_variant, intron_variant	Intron 16 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150548 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432246 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 711200

African (AFR) AF: 0.00 AC: 0 AN: 31724

American (AMR) AF: 0.00 AC: 0 AN: 39544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39194

South Asian (SAS) AF: 0.00 AC: 0 AN: 80732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4894

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1099652

Other (OTH) AF: 0.00 AC: 0 AN: 58902

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150548 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73398

African (AFR) AF: 0.0000244 AC: 1 AN: 41010

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67572

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Benign:1

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.8
DANN	Benign	0.68
PhyloP100		-0.012
PromoterAI		-0.010	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000090
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs1555286676; hg19: chr13-48955375;