rs1369823342

Variant names:

• chr13-48304026-C-T
• rs1369823342
• NM_000321.3:c.114C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000321.3(RB1):​c.114C>T​(p.Gly38Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,311,062 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: 0.0000015 (0 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.750
• 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 13-48304026-C-T is Benign according to our data. Variant chr13-48304026-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 527951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.75 with no splicing effect.

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.114C>T	p.Gly38Gly	synonymous	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.114C>T	p.Gly38Gly	synonymous	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.114C>T	p.Gly38Gly	synonymous	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.114C>T	p.Gly38Gly	synonymous	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.114C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.114C>T	p.Gly38Gly	synonymous	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 67568 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1311062 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 646076

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000382 AC: 1 AN: 26194

American (AMR) AF: 0.00 AC: 0 AN: 23194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22552

East Asian (EAS) AF: 0.00 AC: 0 AN: 29172

South Asian (SAS) AF: 0.00 AC: 0 AN: 70862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3938

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1047978

Other (OTH) AF: 0.00 AC: 0 AN: 54408

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Retinoblastoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		0.75
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs1369823342; hg19: chr13-48878162;