Genetic Variant NM_000321.3:c.-160T>C (chr13-48303753-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000321.3(RB1):c.-160T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000941 in 1,169,526 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

RB1
NM_000321.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.430

Publications

0 publications found

Variant links:

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 links:

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

RB1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BS2

High AC in GnomAdExome4 at 9 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1	NM_000321.3	MANE Select	c.-160T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	NP_000312.2	P06400
RB1	NM_000321.3	MANE Select	c.-160T>C	5_prime_UTR	Exon 1 of 27	NP_000312.2	P06400
RB1	NM_001407165.1		c.-160T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.-160T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	ENSP00000267163.4	P06400
RB1	ENST00000267163.6	TSL:1 MANE Select	c.-160T>C	5_prime_UTR	Exon 1 of 27	ENSP00000267163.4	P06400
RB1	ENST00000924352.1		c.-160T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000885

AC:

AN:

1017474

Hom.:

Cov.:

AF XY:

0.00000597

AC XY:

AN XY:

502298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19856

American (AMR)

AF:

0.00

AC:

AN:

14814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17874

East Asian (EAS)

AF:

0.00

AC:

AN:

26426

South Asian (SAS)

AF:

0.00

AC:

AN:

58084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3124

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

803082

Other (OTH)

AF:

0.00

AC:

AN:

43852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.43

PromoterAI

0.12

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over