rs958914211

chr13-48465022-G-Achr13-48465022-G-Cchr13-48465022-G-T

Variant summary

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

The NM_000321.3(RB1):c.2236G>A(p.Glu746Lys) variant causes a missense change involving the alteration of a 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E746Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 27)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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 4 ACMG points.

• PM1: In a region_of_interest Domain B (size 131) in uniprot entity RB_HUMAN there are 40 pathogenic changes around while only 13 benign (75%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2236G>A	p.Glu746Lys	missense_variant	22/27	ENST00000267163.6
RB1	NM_001407165.1	c.2236G>A	p.Glu746Lys	missense_variant	22/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2236G>A	p.Glu746Lys	missense_variant	22/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.2236G>A	p.Glu746Lys	missense_variant	22/27
RB1	ENST00000643064.1	c.194+83579G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.4	N;.
REVEL	Pathogenic	0.68
Sift	Benign	0.27	T;.
Sift4G	Uncertain	0.011	D;.
Polyphen		0.95	P;.
Vest4		0.54
MutPred		0.52		Gain of ubiquitination at E746 (P = 0.0117);Gain of ubiquitination at E746 (P = 0.0117);
MVP		0.80
MPC		1.2
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.67
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr13-49039158; COSMIC: COSV57323773;