13-48364894-G-C

Position:

• chr13-48364894-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000321.3(RB1):​c.862G>C​(p.Val288Leu) 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. 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. V288M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.862G>C	p.Val288Leu	missense_variant, splice_region_variant	9/27	ENST00000267163.6
LOC112268118	XR_002957522.2	n.204C>G		non_coding_transcript_exon_variant	3/3
RB1	NM_001407165.1	c.862G>C	p.Val288Leu	missense_variant, splice_region_variant	9/27
RB1	NM_001407166.1	c.862G>C	p.Val288Leu	missense_variant, splice_region_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.862G>C	p.Val288Leu	missense_variant, splice_region_variant	9/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.862G>C	p.Val288Leu	missense_variant, splice_region_variant	9/27

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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.020	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.38		Loss of methylation at K289 (P = 0.0384);Loss of methylation at K289 (P = 0.0384);
MVP		0.93
MPC		1.3
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.67
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		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: chr13-48939030;