chr13-48380182-A-T

Position:

• chr13-48380182-A-T

Variant summary

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

The NM_000321.3(RB1):​c.1439A>T​(p.Asn480Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,454 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 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.1439A>T	p.Asn480Ile	missense_variant	16/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1439A>T	p.Asn480Ile	missense_variant	16/27		NP_001394094.1
RB1	NM_001407166.1	c.1439A>T	p.Asn480Ile	missense_variant	16/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1439A>T	p.Asn480Ile	missense_variant	16/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1439A>T	p.Asn480Ile	missense_variant	16/27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447454 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.046	D;.
Polyphen		0.92	P;.
Vest4		0.73
MutPred		0.56		Gain of catalytic residue at I481 (P = 9e-04);Gain of catalytic residue at I481 (P = 9e-04);
MVP		0.86
MPC		1.2
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.90
gMVP		0.21

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48954318;