chr13-48465007-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000321.3(RB1):​c.2221C>G​(p.Arg741Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000117 in 856,106 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 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 3 benign, 25 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage

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>G	p.Arg741Gly	missense	Exon 22 of 27	NP_000312.2
	RB1	NM_001407165.1		c.2221C>G	p.Arg741Gly	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>G	p.Arg741Gly	missense	Exon 22 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*1589C>G		non_coding_transcript_exon	Exon 17 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*1589C>G		3_prime_UTR	Exon 17 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111192 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

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245580 AF XY: 0.00

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: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000117 AC: 1 AN: 856106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 440210

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: 16780

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: 0.00000166 AC: 1 AN: 601712

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

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 111192 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 50510

African (AFR) AF: 0.00 AC: 0 AN: 31116

American (AMR) AF: 0.00 AC: 0 AN: 7780

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3374

South Asian (SAS) AF: 0.00 AC: 0 AN: 3304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57266

Other (OTH) AF: 0.00 AC: 0 AN: 1452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.60
Sift	Benign	0.26	T
Sift4G	Benign	0.35	T
Polyphen		0.88	P
Vest4		0.68
MutPred		0.51		Loss of helix (P = 0.0237)
MVP		0.89
MPC		1.2
ClinPred		0.77	D
GERP RS		4.6
Varity_R		0.64
gMVP		0.60
Mutation Taster		=54/46	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;