chr13-48303942-C-T

Variant names:

• chr13-48303942-C-T
• rs530961288
• NM_000321.3:c.30C>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.30C>T​(p.Ala10Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,357,376 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. A10A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.508
• Publications: 1 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-DT (HGNC:42778): (RB1 divergent transcript)

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=-0.6).
• BP6: Variant 13-48303942-C-T is Benign according to our data. Variant chr13-48303942-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.508 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.30C>T	p.Ala10Ala	synonymous	Exon 1 of 27	NP_000312.2
	RB1	NM_001407165.1		c.30C>T	p.Ala10Ala	synonymous	Exon 1 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.30C>T	p.Ala10Ala	synonymous	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.30C>T	p.Ala10Ala	synonymous	Exon 1 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.30C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
	RB1	ENST00000924352.1		c.30C>T	p.Ala10Ala	synonymous	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000295 AC: 4 AN: 1357376 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 669576

African (AFR) AF: 0.00 AC: 0 AN: 27776

American (AMR) AF: 0.00 AC: 0 AN: 33238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24198

East Asian (EAS) AF: 0.00 AC: 0 AN: 32376

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4012

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1068476

Other (OTH) AF: 0.00 AC: 0 AN: 56552

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	-0.60
CADD	Benign	10
DANN	Benign	0.89
PhyloP100		-0.51
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs530961288; hg19: chr13-48878078;