chr13-48381322-C-G

Variant names:

• chr13-48381322-C-G
• rs4151539
• NM_000321.3:c.1574C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000321.3(RB1):​c.1574C>G​(p.Ala525Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,611,652 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A525T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (7 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 7.57
• Publications: 20 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011211336).
• BP6: Variant 13-48381322-C-G is Benign according to our data. Variant chr13-48381322-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00577 (876/151926) while in subpopulation AFR AF = 0.0202 (836/41440). AF 95% confidence interval is 0.019. There are 11 homozygotes in GnomAd4. There are 387 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 876 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.1574C>G	p.Ala525Gly	missense	Exon 17 of 27	NP_000312.2
	RB1	NM_001407165.1		c.1574C>G	p.Ala525Gly	missense	Exon 17 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.1574C>G	p.Ala525Gly	missense	Exon 17 of 17	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1574C>G	p.Ala525Gly	missense	Exon 17 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*942C>G		non_coding_transcript_exon	Exon 12 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*942C>G		3_prime_UTR	Exon 12 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 875 AN: 151808 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000588

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00153 AC: 381 AN: 249146 AF XY: 0.00110

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000619 AC: 903 AN: 1459726 Hom.: 7 Cov.: 32 AF XY: 0.000551 AC XY: 400 AN XY: 726022

African (AFR) AF: 0.0204 AC: 680 AN: 33382

American (AMR) AF: 0.00162 AC: 72 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85754

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5740

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111074

Other (OTH) AF: 0.00121 AC: 73 AN: 60308

GnomAD4 genome AF: 0.00577 AC: 876 AN: 151926 Hom.: 11 Cov.: 32 AF XY: 0.00521 AC XY: 387 AN XY: 74214

African (AFR) AF: 0.0202 AC: 836 AN: 41440

American (AMR) AF: 0.00177 AC: 27 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67964

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.00687

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.00145 AC: 5 AN: 3470

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Retinoblastoma (8)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.76
Sift	Benign	0.099	T
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.80
MPC		0.90
ClinPred		0.025	T
GERP RS		5.2
PromoterAI		-0.0059	Neutral
Varity_R		0.74
gMVP		0.51
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4151539; hg19: chr13-48955458;