rs878853950

Positions:

• chr13-48465211-A-C
• chr13-48465211-A-G
• chr13-48465211-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000321.3(RB1):​c.2332A>C​(p.Thr778Pro) 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. 12/21 in silico tools predict 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: 28)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest Domain C; mediates interaction with E4F1 (size 157) in uniprot entity RB_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27337867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2332A>C	p.Thr778Pro	missense_variant	23/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2332A>C	p.Thr778Pro	missense_variant	23/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2332A>C	p.Thr778Pro	missense_variant	23/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2332A>C	p.Thr778Pro	missense_variant	23/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+83768A>C		intron_variant				ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.32	T;.
Sift4G	Benign	0.20	T;.
Polyphen		0.074	B;.
Vest4		0.31
MutPred		0.46		Gain of catalytic residue at P776 (P = 2e-04);Gain of catalytic residue at P776 (P = 2e-04);
MVP		0.84
MPC		1.3
ClinPred		0.74	D
GERP RS		3.5
Varity_R		0.69
gMVP		0.47

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-49039347;