13-48368550-G-C

Position:

• chr13-48368550-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000321.3(RB1):​c.1073G>C​(p.Arg358Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R358G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.460

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17841077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1073G>C	p.Arg358Pro	missense_variant	11/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1073G>C	p.Arg358Pro	missense_variant	11/27		NP_001394094.1
RB1	NM_001407166.1	c.1073G>C	p.Arg358Pro	missense_variant	11/17		NP_001394095.1
LOC112268118	XR_002957522.2	n.122-3574C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1073G>C	p.Arg358Pro	missense_variant	11/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1073G>C	p.Arg358Pro	missense_variant	11/27			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	0.35
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	0.024	D
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.58
Sift	Benign	0.14	T;.
Sift4G	Uncertain	0.036	D;.
Polyphen		0.91	P;.
Vest4		0.40
MutPred		0.44		Gain of catalytic residue at P357 (P = 0.0016);Gain of catalytic residue at P357 (P = 0.0016);
MVP		0.88
MPC		0.82
ClinPred		0.48	T
GERP RS		-2.0
Varity_R		0.22
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr13-48942686;