13-48367518-G-C

Position:

• chr13-48367518-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000321.3(RB1):​c.964G>C​(p.Glu322Gln) variant causes a missense change. 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: 4.47

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 2 ACMG points.

• 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.964G>C	p.Glu322Gln	missense_variant	10/27	ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2	n.122-2542C>G		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1	c.964G>C	p.Glu322Gln	missense_variant	10/27		NP_001394094.1
RB1	NM_001407166.1	c.964G>C	p.Glu322Gln	missense_variant	10/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.964G>C	p.Glu322Gln	missense_variant	10/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.964G>C	p.Glu322Gln	missense_variant	10/27			ENSP00000497193

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Pathogenic	0.65
Sift	Benign	0.035	D;.
Sift4G	Benign	0.15	T;.
Polyphen		0.67	P;.
Vest4		0.56
MutPred		0.35		Loss of ubiquitination at K327 (P = 0.0342);Loss of ubiquitination at K327 (P = 0.0342);
MVP		0.85
MPC		1.1
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.34
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776534331; hg19: chr13-48941654;