rs373623059

Variant names:

• chr13-48373440-T-C
• rs373623059
• NM_000321.3:c.1163T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-48373440-T-C
• chr13-48373440-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000321.3(RB1):​c.1163T>C​(p.Ile388Thr) 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 1,446,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. I388S) 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.42

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]

LOC112268118 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28756273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1163T>C	p.Ile388Thr	missense_variant	Exon 12 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1163T>C	p.Ile388Thr	missense_variant	Exon 12 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1163T>C	p.Ile388Thr	missense_variant	Exon 12 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	n.121+720A>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1163T>C	p.Ile388Thr	missense_variant	Exon 12 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1163T>C	p.Ile388Thr	missense_variant	Exon 12 of 27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446614 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 720556

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Jun 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 388 of the RB1 protein (p.Ile388Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578835). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I388T variant (also known as c.1163T>C), located in coding exon 12 of the RB1 gene, results from a T to C substitution at nucleotide position 1163. The isoleucine at codon 388 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.24
Sift	Benign	0.34	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.42	B;.
Vest4		0.55
MutPred		0.68		Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);
MVP		0.78
MPC		0.57
ClinPred		0.62	D
GERP RS		4.4
Varity_R		0.23
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs373623059; hg19: chr13-48947576;