13-48477403-G-C

Position:

• chr13-48477403-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000321.3(RB1):​c.2712G>C​(p.Met904Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense, splice_region
• Scores: Splicing: ADA: 0.9852
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.16

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Domain C; mediates interaction with E4F1 (size 157) in uniprot entity RB_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2712G>C	p.Met904Ile	missense_variant, splice_region_variant	26/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2712G>C	p.Met904Ile	missense_variant, splice_region_variant	26/27		NP_001394094.1
RB1	NM_001407168.1	c.162G>C	p.Met54Ile	missense_variant, splice_region_variant	3/4		NP_001394097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2712G>C	p.Met904Ile	missense_variant, splice_region_variant	26/27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451036 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.77	N;.
REVEL	Uncertain	0.45
Sift	Benign	0.084	T;.
Sift4G	Benign	0.096	T;.
Polyphen		0.064	B;.
Vest4		0.65
MutPred		0.47		Gain of catalytic residue at S906 (P = 0.0022);Gain of catalytic residue at S906 (P = 0.0022);
MVP		0.93
MPC		1.1
ClinPred		0.71	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1461167778; hg19: chr13-49051539; COSMIC: COSV57297074;