13-48304028-C-T

Variant names:

• chr13-48304028-C-T
• rs1180053508
• NM_000321.3:c.116C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000321.3(RB1):​c.116C>T​(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. P39S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.83
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

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

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 39 uncertain in NM_000321.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.24072108).
• BP6: Variant 13-48304028-C-T is Benign according to our data. Variant chr13-48304028-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527911.
• BS2: High AC in GnomAdExome4 at 10 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.116C>T	p.Pro39Leu	missense	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.116C>T	p.Pro39Leu	missense	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.116C>T	p.Pro39Leu	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.116C>T	p.Pro39Leu	missense	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.116C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.116C>T	p.Pro39Leu	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000764 AC: 10 AN: 1308778 Hom.: 0 Cov.: 31 AF XY: 0.00000775 AC XY: 5 AN XY: 644852

African (AFR) AF: 0.0000383 AC: 1 AN: 26142

American (AMR) AF: 0.00 AC: 0 AN: 22834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22472

East Asian (EAS) AF: 0.00 AC: 0 AN: 29048

South Asian (SAS) AF: 0.00 AC: 0 AN: 70510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.00000669 AC: 7 AN: 1046832

Other (OTH) AF: 0.0000368 AC: 2 AN: 54322

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Retinoblastoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.27
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.011	D
Polyphen		0.18	B
Vest4		0.13
MutPred		0.19		Gain of catalytic residue at E34 (P = 0.0773)
MVP		0.80
MPC		0.46
ClinPred		0.63	D
GERP RS		3.8
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.14
gMVP		0.30
Mutation Taster		=94/6	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: rs1180053508; hg19: chr13-48878164;