13-48364930-A-T

Variant names:

• chr13-48364930-A-T
• rs1060503086
• NM_000321.3:c.898A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000321.3(RB1):​c.898A>T​(p.Met300Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M300T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057676703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.898A>T	p.Met300Leu	missense_variant	Exon 9 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.898A>T	p.Met300Leu	missense_variant	Exon 9 of 27		NP_001394094.1
RB1	NM_001407166.1	c.898A>T	p.Met300Leu	missense_variant	Exon 9 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	n.168T>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.898A>T	p.Met300Leu	missense_variant	Exon 9 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416942 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 701190

African (AFR) AF: 0.00 AC: 0 AN: 31892

American (AMR) AF: 0.0000241 AC: 1 AN: 41470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25350

East Asian (EAS) AF: 0.00 AC: 0 AN: 37466

South Asian (SAS) AF: 0.00 AC: 0 AN: 81512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1085026

Other (OTH) AF: 0.00 AC: 0 AN: 58268

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M300L variant (also known as c.898A>T), located in coding exon 9 of the RB1 gene, results from an A to T substitution at nucleotide position 898. The methionine at codon 300 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.74
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-2.2	N;.
PhyloP100		1.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.48	N;.
REVEL	Benign	0.17
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.26
MutPred		0.44		Gain of catalytic residue at S302 (P = 5e-04);Gain of catalytic residue at S302 (P = 5e-04);
MVP		0.58
MPC		0.41
ClinPred		0.18	T
GERP RS		4.3
Varity_R		0.27
gMVP		0.54
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1060503086; hg19: chr13-48939066;