13-48345161-G-C

Variant names:

• chr13-48345161-G-C
• NM_000321.3:c.462G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000321.3(RB1):​c.462G>C​(p.Lys154Asn) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.625

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36552683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.462G>C	p.Lys154Asn	missense_variant	Exon 4 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.462G>C	p.Lys154Asn	missense_variant	Exon 4 of 27		NP_001394094.1
RB1	NM_001407166.1	c.462G>C	p.Lys154Asn	missense_variant	Exon 4 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.462G>C	p.Lys154Asn	missense_variant	Exon 4 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000467505.5	n.138-14856G>C		intron_variant	Intron 1 of 2	1		ENSP00000434702.1
RB1	ENST00000650461.1	c.462G>C	p.Lys154Asn	missense_variant	Exon 4 of 27			ENSP00000497193.1
RB1	ENST00000525036.1	n.624G>C		non_coding_transcript_exon_variant	Exon 4 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.39
Sift	Benign	0.56	T;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.64		Gain of ubiquitination at K153 (P = 0.0356);Gain of ubiquitination at K153 (P = 0.0356);
MVP		0.88
MPC		1.4
ClinPred		0.93	D
GERP RS		2.8
Varity_R		0.20
gMVP		0.59

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: chr13-48919297;