chr13-48377034-G-T

Position:

• chr13-48377034-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000321.3(RB1):​c.1332G>T​(p.Gln444His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 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. Q444R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.95

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 region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-48377033-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1332G>T	p.Gln444His	missense_variant, splice_region_variant	13/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1332G>T	p.Gln444His	missense_variant, splice_region_variant	13/27		NP_001394094.1
RB1	NM_001407166.1	c.1332G>T	p.Gln444His	missense_variant, splice_region_variant	13/17		NP_001394095.1
LOC112268118	XR_002957522.2	n.41-2794C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1332G>T	p.Gln444His	missense_variant, splice_region_variant	13/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1332G>T	p.Gln444His	missense_variant, splice_region_variant	13/27			ENSP00000497193.1

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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.50
MutPred		0.53		Gain of catalytic residue at S443 (P = 0);Gain of catalytic residue at S443 (P = 0);
MVP		0.83
MPC		1.2
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		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: chr13-48951170; COSMIC: COSV57310134; COSMIC: COSV57310134;