rs754183765

Variant names:

• chr13-48476713-T-A
• rs754183765
• NM_000321.3:c.2533T>A

Your query was ambiguous. Multiple possible variants found:

• chr13-48476713-T-A
• chr13-48476713-T-C
• chr13-48476713-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000321.3(RB1):​c.2533T>A​(p.Phe845Ile) variant causes a missense change. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. F845L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.53
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.2533T>A	p.Phe845Ile	missense	Exon 25 of 27	NP_000312.2
	RB1	NM_001407165.1		c.2533T>A	p.Phe845Ile	missense	Exon 25 of 27	NP_001394094.1
	RB1	NM_001407168.1		c.-18T>A		5_prime_UTR	Exon 2 of 4	NP_001394097.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2533T>A	p.Phe845Ile	missense	Exon 25 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*1901T>A		non_coding_transcript_exon	Exon 20 of 22	ENSP00000434702.1
	RB1	ENST00000484879.1	TSL:1	n.267T>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.5	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.96	D
Vest4		0.80
MutPred		0.73		Gain of catalytic residue at G840 (P = 0.0089)
MVP		0.85
MPC		1.2
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.60
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs754183765; hg19: chr13-49050849;