chr13-48303944-C-T

Variant names:

• chr13-48303944-C-T
• rs899323337
• NM_000321.3:c.32C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000321.3(RB1):​c.32C>T​(p.Ala11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 1,509,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.97
• 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-DT (HGNC:42778): (RB1 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.114751935).

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.32C>T	p.Ala11Val	missense	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.32C>T	p.Ala11Val	missense	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.32C>T	p.Ala11Val	missense	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.32C>T	p.Ala11Val	missense	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.32C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.32C>T	p.Ala11Val	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151932 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1357590 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 669668

African (AFR) AF: 0.00 AC: 0 AN: 27782

American (AMR) AF: 0.00 AC: 0 AN: 33266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24204

East Asian (EAS) AF: 0.00 AC: 0 AN: 32412

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068592

Other (OTH) AF: 0.00 AC: 0 AN: 56556

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151932 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41302

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67954

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.18	N
REVEL	Benign	0.11
Sift	Benign	0.34	T
Sift4G	Benign	0.41	T
Polyphen		0.036	B
Vest4		0.20
MutPred		0.34		Loss of helix (P = 0.0626)
MVP		0.73
MPC		0.44
ClinPred		0.18	T
GERP RS		3.4
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.066
gMVP		0.17
Mutation Taster		=88/12	polymorphism

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: rs899323337; hg19: chr13-48878080;