Genetic Variant ENST00000433480.4:n.46C>G (chr13-48303678-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000433480.4(RB1-DT):n.46C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000047 in 425,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

RB1-DT
ENST00000433480.4 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0570

Publications

0 publications found

Variant links:

Genes affected

RB1-DT (HGNC:42778): (RB1 divergent transcript)

RB1-DT links:

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

RB1 links:

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ACMG classification

Classification was made for transcript

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=-0.61).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000433480.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1-DT	NR_046414.2		n.25C>G	non_coding_transcript_exon	Exon 1 of 3
RB1	NM_000321.3	MANE Select	c.-235G>C	upstream_gene	N/A	NP_000312.2	P06400
RB1	NM_001407165.1		c.-235G>C	upstream_gene	N/A	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
RB1-DT	ENST00000433480.4	TSL:1	n.46C>G	non_coding_transcript_exon	Exon 1 of 3
RB1-DT	ENST00000436963.3	TSL:3	n.43C>G	non_coding_transcript_exon	Exon 1 of 3
RB1-DT	ENST00000700890.2		n.46C>G	non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000470

AC:

AN:

425936

Hom.:

Cov.:

AF XY:

0.00000897

AC XY:

AN XY:

222902

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

8352

American (AMR)

AF:

0.00

AC:

AN:

9404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11938

East Asian (EAS)

AF:

0.00

AC:

AN:

23084

South Asian (SAS)

AF:

0.0000497

AC:

AN:

40248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26938

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1852

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

280188

Other (OTH)

AF:

0.00

AC:

AN:

23932

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.5

(source)

DANN

Benign

0.84

PhyloP100

0.057

PromoterAI

0.035

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over