rs1039235140

Variant names:

• chr13-48360007-T-C
• rs1039235140
• NM_000321.3:c.608-10T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000321.3(RB1):​c.608-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RB1 NM_000321.3 intron
• Scores: Splicing: ADA: 0.002500
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.39
• 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: Orphanet, Labcorp Genetics (formerly Invitae), 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 13-48360007-T-C is Benign according to our data. Variant chr13-48360007-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 416494.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.608-10T>C		intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.608-10T>C		intron	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.608-10T>C		intron	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.608-10T>C		intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.138-10T>C		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.731-10T>C		intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459212 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726030

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.0000224 AC: 1 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111080

Other (OTH) AF: 0.0000166 AC: 1 AN: 60268

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.73
PhyloP100		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.068
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: rs1039235140; hg19: chr13-48934143;