chr13-48465285-G-A

Variant names:

• chr13-48465285-G-A
• rs866638680
• NM_000321.3:c.2406G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000321.3(RB1):​c.2406G>A​(p.Gly802Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,832 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G802G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0520
• 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), Ambry Genetics, G2P
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 13-48465285-G-A is Benign according to our data. Variant chr13-48465285-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 458147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

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.2406G>A	p.Gly802Gly	synonymous	Exon 23 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.2406G>A	p.Gly802Gly	synonymous	Exon 23 of 27	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2406G>A	p.Gly802Gly	synonymous	Exon 23 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*1774G>A		non_coding_transcript_exon	Exon 18 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*1774G>A		3_prime_UTR	Exon 18 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251426 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459832 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 726366

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110152

Other (OTH) AF: 0.0000332 AC: 2 AN: 60326

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Retinoblastoma (3)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	RB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		0.052

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: rs866638680; hg19: chr13-49039421; COSMIC: COSV57322459;