rs117865557

Positions:

• chr13-48373417-C-G
• chr13-48373417-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000321.3(RB1):​c.1140C>G​(p.Asn380Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.806

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]

LOC112268118 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1140C>G	p.Asn380Lys	missense_variant	12/27	ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2	n.121+743G>C		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1	c.1140C>G	p.Asn380Lys	missense_variant	12/27		NP_001394094.1
RB1	NM_001407166.1	c.1140C>G	p.Asn380Lys	missense_variant	12/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1140C>G	p.Asn380Lys	missense_variant	12/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.1140C>G	p.Asn380Lys	missense_variant	12/27			ENSP00000497193

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.
Eigen	Benign	-0.054
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.036	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.80	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.39
Sift	Benign	0.036	D;.
Sift4G	Uncertain	0.034	D;.
Polyphen		0.77	P;.
Vest4		0.76
MutPred		0.62		Gain of catalytic residue at V375 (P = 0.0028);Gain of catalytic residue at V375 (P = 0.0028);
MVP		0.84
MPC		1.2
ClinPred		0.89	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.57

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: chr13-48947553;