rs587778638

Variant names:

• chr13-48303955-G-A
• rs587778638
• NM_000321.3:c.43G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-48303955-G-A
• chr13-48303955-G-C
• chr13-48303955-G-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.43G>A​(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A15G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.438
• Publications: 2 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=0.08893114).

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.43G>A	p.Ala15Thr	missense	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.43G>A	p.Ala15Thr	missense	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.43G>A	p.Ala15Thr	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.43G>A	p.Ala15Thr	missense	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.43G>A		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.43G>A	p.Ala15Thr	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354106 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 668128

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

African (AFR) AF: 0.00 AC: 0 AN: 25642

American (AMR) AF: 0.00 AC: 0 AN: 32982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24164

East Asian (EAS) AF: 0.00 AC: 0 AN: 32384

South Asian (SAS) AF: 0.00 AC: 0 AN: 76544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068142

Other (OTH) AF: 0.00 AC: 0 AN: 56234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.44
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.17
Sift	Benign	0.57	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.35		Gain of catalytic residue at P20 (P = 6e-04)
MVP		0.55
MPC		0.43
ClinPred		0.056	T
GERP RS		0.54
PromoterAI		0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.039
gMVP		0.19
Mutation Taster		=94/6	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: rs587778638; hg19: chr13-48878091; COSMIC: COSV57297396;