13-48380182-A-C

Variant names:

• chr13-48380182-A-C
• rs1555286598
• NM_000321.3:c.1439A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000321.3(RB1):​c.1439A>C​(p.Asn480Thr) 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. 14/22 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. N480S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 24 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2559208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1439A>C	p.Asn480Thr	missense_variant	Exon 16 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1439A>C	p.Asn480Thr	missense_variant	Exon 16 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1439A>C	p.Asn480Thr	missense_variant	Exon 16 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1439A>C	p.Asn480Thr	missense_variant	Exon 16 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.00073	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.
Eigen	Benign	-0.024
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		3.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.29
Sift	Benign	0.030	D;.
Sift4G	Benign	0.19	T;.
Polyphen		0.45	B;.
Vest4		0.49
MutPred		0.55		Gain of catalytic residue at I481 (P = 7e-04);Gain of catalytic residue at I481 (P = 7e-04);
MVP		0.83
MPC		0.56
ClinPred		0.51	D
GERP RS		3.5
Varity_R		0.45
gMVP		0.063
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs1555286598; hg19: chr13-48954318;