rs529366765

Variant names:

• chr13-48465007-C-A
• rs529366765
• NM_000321.3:c.2221C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-48465007-C-A
• chr13-48465007-C-G
• chr13-48465007-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000321.3(RB1):​c.2221C>A​(p.Arg741Ser) variant causes a missense change. In-silico tool predicts 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. R741H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

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

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 25 uncertain in NM_000321.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.24878275).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.2221C>A	p.Arg741Ser	missense	Exon 22 of 27	NP_000312.2
	RB1	NM_001407165.1		c.2221C>A	p.Arg741Ser	missense	Exon 22 of 27	NP_001394094.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2221C>A	p.Arg741Ser	missense	Exon 22 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*1589C>A		non_coding_transcript_exon	Exon 17 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*1589C>A		3_prime_UTR	Exon 17 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111194 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 856100 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 440208

African (AFR) AF: 0.00 AC: 0 AN: 24560

American (AMR) AF: 0.00 AC: 0 AN: 38166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16778

East Asian (EAS) AF: 0.00 AC: 0 AN: 24132

South Asian (SAS) AF: 0.00 AC: 0 AN: 72132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 601708

Other (OTH) AF: 0.00 AC: 0 AN: 35116

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 111276 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 50574

African (AFR) AF: 0.00 AC: 0 AN: 31178

American (AMR) AF: 0.00 AC: 0 AN: 7786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3140

East Asian (EAS) AF: 0.00 AC: 0 AN: 3378

South Asian (SAS) AF: 0.00 AC: 0 AN: 3314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57262

Other (OTH) AF: 0.00 AC: 0 AN: 1460

Alfa AF: 0.0000202 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Benign	0.45
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	-0.58	N
PhyloP100		3.8
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.44
Sift	Benign	0.87	T
Sift4G	Benign	0.35	T
Polyphen		0.23	B
Vest4		0.64
MutPred		0.47		Gain of ubiquitination at K740 (P = 0.0501)
MVP		0.94
MPC		1.0
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.61
gMVP		0.51
Mutation Taster		=56/44	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: rs529366765; hg19: chr13-49039143; COSMIC: COSV57300915;