rs898303682

Variant names:

• chr13-48303925-A-C
• rs898303682
• NM_000321.3:c.13A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-48303925-A-C
• chr13-48303925-A-G
• chr13-48303925-A-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.13A>C​(p.Thr5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T5S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.376
• Publications: 7 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=0.112885684).

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.13A>C	p.Thr5Pro	missense	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.13A>C	p.Thr5Pro	missense	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.13A>C	p.Thr5Pro	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.13A>C	p.Thr5Pro	missense	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.13A>C		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.13A>C	p.Thr5Pro	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000438 AC: 59 AN: 1347404 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 27 AN XY: 665064

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

African (AFR) AF: 0.000109 AC: 3 AN: 27418

American (AMR) AF: 0.0000303 AC: 1 AN: 33010

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 7 AN: 23640

East Asian (EAS) AF: 0.000190 AC: 6 AN: 31542

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33372

Middle Eastern (MID) AF: 0.000255 AC: 1 AN: 3924

European-Non Finnish (NFE) AF: 0.0000367 AC: 39 AN: 1062046

Other (OTH) AF: 0.0000179 AC: 1 AN: 55848

⚠️ 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

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Retinoblastoma (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.67
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.38
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.13
Sift	Benign	0.28	T
Sift4G	Benign	0.38	T
Polyphen		0.037	B
Vest4		0.19
MutPred		0.33		Gain of catalytic residue at P2 (P = 0)
MVP		0.77
MPC		0.58
ClinPred		0.12	T
GERP RS		-3.0
PromoterAI		0.069	Neutral
Varity_R		0.11
gMVP		0.094
Mutation Taster		=96/4	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: rs898303682; hg19: chr13-48878061;