rs587778637

Variant names:

• chr13-48303971-C-T
• rs587778637
• NM_000321.3:c.59C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000321.3(RB1):​c.59C>T​(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,503,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3 O:1
• Conservation: PhyloP100: 1.47
• Publications: 5 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-DT (HGNC:42778): (RB1 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 13-48303971-C-T is Benign according to our data. Variant chr13-48303971-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135115.
• BS2: High AC in GnomAd4 at 18 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.59C>T	p.Pro20Leu	missense	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.59C>T	p.Pro20Leu	missense	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.59C>T	p.Pro20Leu	missense	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.59C>T	p.Pro20Leu	missense	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.59C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.59C>T	p.Pro20Leu	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000128 AC: 13 AN: 101296 AF XY: 0.000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000973

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000146 AC: 198 AN: 1351810 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 93 AN XY: 666756

African (AFR) AF: 0.000109 AC: 3 AN: 27504

American (AMR) AF: 0.0000626 AC: 2 AN: 31970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23968

East Asian (EAS) AF: 0.00 AC: 0 AN: 31984

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33846

Middle Eastern (MID) AF: 0.000498 AC: 2 AN: 4018

European-Non Finnish (NFE) AF: 0.000163 AC: 174 AN: 1066164

Other (OTH) AF: 0.000285 AC: 16 AN: 56232

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67942

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000235 Hom.: 0

Bravo AF: 0.000110

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Retinoblastoma (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	not specified (2)
-	1	-	RB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.062
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.34	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.21
MVP		0.96
MPC		0.45
ClinPred		0.18	T
GERP RS		2.9
PromoterAI		0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.12
gMVP		0.36
Mutation Taster		=90/10	polymorphism

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: rs587778637; hg19: chr13-48878107; COSMIC: COSV105859610;