13-48304028-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000321.3(RB1):​c.116C>A​(p.Pro39Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,308,778 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. 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. P39L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83
• 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 2 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24464676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.116C>A	p.Pro39Gln	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.116C>A	p.Pro39Gln	missense_variant	Exon 1 of 27		NP_001394094.1
RB1	NM_001407166.1	c.116C>A	p.Pro39Gln	missense_variant	Exon 1 of 17		NP_001394095.1
RB1	NM_001407167.1	c.116C>A	p.Pro39Gln	missense_variant	Exon 1 of 3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.116C>A	p.Pro39Gln	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1308778 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644852

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26142

American (AMR) AF: 0.0000438 AC: 1 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: 0.0000142 AC: 1 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: 0.00 AC: 0 AN: 1046832

Other (OTH) AF: 0.00 AC: 0 AN: 54322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	0.042	D
MutationAssessor	Benign	0.69	N;.;.
PhyloP100		2.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.18	N;.;.
REVEL	Benign	0.25
Sift	Benign	0.056	T;.;.
Sift4G	Uncertain	0.055	T;.;.
Polyphen		0.089	B;.;.
Vest4		0.15
MutPred		0.19		Gain of solvent accessibility (P = 0.0648);Gain of solvent accessibility (P = 0.0648);Gain of solvent accessibility (P = 0.0648);
MVP		0.76
MPC		0.47
ClinPred		0.69	D
GERP RS		3.8
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.11
gMVP		0.33
Mutation Taster		=97/3	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;