13-48379606-G-C

Variant names:

• chr13-48379606-G-C
• NM_000321.3:c.1345G>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Moderate

The NM_000321.3(RB1):​c.1345G>C​(p.Gly449Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G449E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09

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 Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_000321.3 (RB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 428669
• PM1: In a helix (size 29) in uniprot entity RB_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) 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 chr13-48379607-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2736027.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1345G>C	p.Gly449Arg	missense_variant	Exon 14 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1345G>C	p.Gly449Arg	missense_variant	Exon 14 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1345G>C	p.Gly449Arg	missense_variant	Exon 14 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	n.40+229C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1345G>C	p.Gly449Arg	missense_variant	Exon 14 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1345G>C	p.Gly449Arg	missense_variant	Exon 14 of 27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.80		Gain of catalytic residue at Q444 (P = 0);Gain of catalytic residue at Q444 (P = 0);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr13-48953742; COSMIC: COSV57306967; COSMIC: COSV57306967;