chr13-48381322-C-A

Variant names:

• chr13-48381322-C-A
• rs4151539
• NM_000321.3:c.1574C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000321.3(RB1):​c.1574C>A​(p.Ala525Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A525T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 20 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

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.1574C>A	p.Ala525Asp	missense	Exon 17 of 27	NP_000312.2
	RB1	NM_001407165.1		c.1574C>A	p.Ala525Asp	missense	Exon 17 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.1574C>A	p.Ala525Asp	missense	Exon 17 of 17	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1574C>A	p.Ala525Asp	missense	Exon 17 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*942C>A		non_coding_transcript_exon	Exon 12 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*942C>A		3_prime_UTR	Exon 12 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459728 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726024

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 85754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111076

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.74		Gain of catalytic residue at K524 (P = 0.0021)
MVP		0.96
MPC		1.5
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		0.0065	Neutral
Varity_R		0.98
gMVP		0.92
Mutation Taster		=3/97	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: rs4151539; hg19: chr13-48955458;