rs367960214

Positions:

• chr13-48360067-C-G
• chr13-48360067-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000321.3(RB1):​c.658C>G​(p.Leu220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L220I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.342

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-48360067-C-G is Pathogenic according to our data. Variant chr13-48360067-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1678695.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.658C>G	p.Leu220Val	missense_variant	7/27	ENST00000267163.6
RB1	NM_001407165.1	c.658C>G	p.Leu220Val	missense_variant	7/27
RB1	NM_001407166.1	c.658C>G	p.Leu220Val	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.658C>G	p.Leu220Val	missense_variant	7/27	1	NM_000321.3	P1
RB1	ENST00000467505.5	c.*26C>G		3_prime_UTR_variant, NMD_transcript_variant	2/3	1
RB1	ENST00000650461.1	c.658C>G	p.Leu220Val	missense_variant	7/27
RB1	ENST00000525036.1	n.820C>G		non_coding_transcript_exon_variant	7/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2022

Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19339519, 21654082, 25151137, 18181215, 18449911, 17996702, 30031154, 28575107, 31997559, 23516486) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.7	N;.
REVEL	Pathogenic	0.74
Sift	Benign	0.042	D;.
Sift4G	Benign	0.072	T;.
Polyphen		0.98	D;.
Vest4		0.73
MutPred		0.38		Gain of catalytic residue at M219 (P = 0);Gain of catalytic residue at M219 (P = 0);
MVP		0.77
MPC		1.3
ClinPred		0.93	D
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -1

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: chr13-48934203;