rs776307088

Variant names:

• chr13-48362878-C-T
• rs776307088
• NM_000321.3:c.782C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-48362878-C-T
• chr13-48362878-C-G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000321.3(RB1):​c.782C>T​(p.Ala261Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A261T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.39
• Publications: 1 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2601713).
• BP6: Variant 13-48362878-C-T is Benign according to our data. Variant chr13-48362878-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 580457.

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.782C>T	p.Ala261Val	missense	Exon 8 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.782C>T	p.Ala261Val	missense	Exon 8 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.782C>T	p.Ala261Val	missense	Exon 8 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.782C>T	p.Ala261Val	missense	Exon 8 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*150C>T		non_coding_transcript_exon	Exon 3 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*150C>T		3_prime_UTR	Exon 3 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251186 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Retinoblastoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T
Sift4G	Benign	0.21	T
Polyphen		0.062	B
Vest4		0.12
MutPred		0.36		Gain of catalytic residue at R259 (P = 0.0189)
MVP		0.75
MPC		0.50
ClinPred		0.23	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.29
Mutation Taster		=91/9	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: rs776307088; hg19: chr13-48937014;