13-48380073-T-G

Variant names:

• chr13-48380073-T-G
• rs578226820
• NM_000321.3:c.1410T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_000321.3(RB1):​c.1410T>G​(p.Ile470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000793 in 1,386,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. I470V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.18
• Publications: 4 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

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000321.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.17707056).
• BS2: High AC in GnomAdExome4 at 8 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.1410T>G	p.Ile470Met	missense	Exon 15 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1410T>G	p.Ile470Met	missense	Exon 15 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1410T>G	p.Ile470Met	missense	Exon 15 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.1410T>G	p.Ile470Met	missense	Exon 15 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*778T>G		non_coding_transcript_exon	Exon 10 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*778T>G		3_prime_UTR	Exon 10 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150578 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000728

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000745 AC: 1 AN: 134210 AF XY: 0.0000136

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000647 AC: 8 AN: 1236002 Hom.: 0 Cov.: 22 AF XY: 0.00000650 AC XY: 4 AN XY: 615652

African (AFR) AF: 0.000263 AC: 7 AN: 26632

American (AMR) AF: 0.00 AC: 0 AN: 27306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22676

East Asian (EAS) AF: 0.00 AC: 0 AN: 34104

South Asian (SAS) AF: 0.00 AC: 0 AN: 67262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3564

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 957374

Other (OTH) AF: 0.00 AC: 0 AN: 51534

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150578 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73502

African (AFR) AF: 0.0000728 AC: 3 AN: 41190

American (AMR) AF: 0.00 AC: 0 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67686

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	1	Retinoblastoma (2)
-	1	-	Malignant tumor of urinary bladder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.012
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.76	N
PhyloP100		1.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.26
Sift	Benign	0.060	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.68	P
Vest4		0.20
MutPred		0.51		Gain of disorder (P = 0.0349)
MVP		0.81
MPC		0.87
ClinPred		0.18	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.16
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs578226820; hg19: chr13-48954209; COSMIC: COSV99924044; COSMIC: COSV99924044;