13-48456349-G-T

Position:

• chr13-48456349-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.1960G>T​(p.Val654Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.92

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]

RB1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 24) in uniprot entity RB_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48456349-G-T is Pathogenic according to our data. Variant chr13-48456349-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3237045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48456349-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1960G>T	p.Val654Leu	missense_variant, splice_region_variant	19/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1960G>T	p.Val654Leu	missense_variant, splice_region_variant	19/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1960G>T	p.Val654Leu	missense_variant, splice_region_variant	19/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1960G>T	p.Val654Leu	missense_variant, splice_region_variant	19/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+74906G>T		intron_variant				ENSP00000496005.1
RB1	ENST00000480491.1	n.*42G>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	May 20, 2024	Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PVS1, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Swedish National ChiCaP Initative, Genomic Medicine Sweden	May 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.48
Sift	Benign	0.28	T;.
Sift4G	Benign	0.97	T;.
Polyphen		0.35	B;.
Vest4		0.44
MutPred		0.78		Gain of catalytic residue at Y659 (P = 0.0117);Gain of catalytic residue at Y659 (P = 0.0117);
MVP		0.97
MPC		1.3
ClinPred		0.86	D
GERP RS		6.0
Varity_R		0.58
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 0

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: chr13-49030485; COSMIC: COSV57322012; COSMIC: COSV57322012;