rs201458896

Variant names:

• chr13-48380211-G-A
• rs201458896
• NM_000321.3:c.1468G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-48380211-G-A
• chr13-48380211-G-C
• chr13-48380211-G-T

Variant summary

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

The NM_000321.3(RB1):​c.1468G>A​(p.Ala490Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,605,006 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A490S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:2
• Conservation: PhyloP100: 7.10
• Publications: 6 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 -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 27 uncertain in NM_000321.3
• BS2: High AC in GnomAdExome4 at 21 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.1468G>A	p.Ala490Thr	missense	Exon 16 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1468G>A	p.Ala490Thr	missense	Exon 16 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1468G>A	p.Ala490Thr	missense	Exon 16 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.1468G>A	p.Ala490Thr	missense	Exon 16 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*836G>A		non_coding_transcript_exon	Exon 11 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*836G>A		3_prime_UTR	Exon 11 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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: 0.0000242 AC: 6 AN: 247962 AF XY: 0.0000298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000276

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1454706 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 723682

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26014

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39448

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.000190 AC: 1 AN: 5252

European-Non Finnish (NFE) AF: 0.00000993 AC: 11 AN: 1107466

Other (OTH) AF: 0.0000167 AC: 1 AN: 60034

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150300 Hom.: 0 Cov.: 31 AF XY: 0.0000273 AC XY: 2 AN XY: 73218

African (AFR) AF: 0.0000245 AC: 1 AN: 40858

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67734

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000152 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

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)
-	1	-	not provided (1)
1	-	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.95
MPC		1.2
ClinPred		0.51	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.44
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201458896; hg19: chr13-48954347; COSMIC: COSV99926212; COSMIC: COSV99926212;