rs373623059

Variant names:

• chr13-48373440-T-C
• rs373623059
• NM_000321.3:c.1163T>C
• RB1 p.Ile388Thr

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 13 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• retinoblastoma

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

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

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.1163T>C	p.Ile388Thr	missense	Exon 12 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1163T>C	p.Ile388Thr	missense	Exon 12 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1163T>C	p.Ile388Thr	missense	Exon 12 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.1163T>C	p.Ile388Thr	missense	Exon 12 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*531T>C		non_coding_transcript_exon	Exon 7 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*531T>C		3_prime_UTR	Exon 7 of 22	ENSP00000434702.1	Q92728

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

⚠️ 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: 33130

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00 AC: 0 AN: 85820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098576

Other (OTH) AF: 0.00 AC: 0 AN: 59900

⚠️ 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.24
Sift	Benign	0.34	T
Sift4G	Benign	1.0	T
Varity_R		0.23
gMVP		0.44
Mutation Taster		=60/40	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373623059;

hg19: chr13-48947576;