13-48345222-T-G

Variant names:

• chr13-48345222-T-G
• rs198617
• NM_000321.3:c.500+23T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000321.3(RB1):​c.500+23T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.974 in 1,606,016 control chromosomes in the GnomAD database, including 762,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66838 hom., cov: 31)
  • Exomes 𝑓: 0.98 (695635 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.319
• Publications: 16 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), 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 (BayesDel_noAF=-0.96).
• BP6: Variant 13-48345222-T-G is Benign according to our data. Variant chr13-48345222-T-G is described in ClinVar as Benign. ClinVar VariationId is 255825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

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.500+23T>G		intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.500+23T>G		intron	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.500+23T>G		intron	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.500+23T>G		intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.138-14795T>G		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.500+23T>G		intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142083 AN: 152050 Hom.: 66798 Cov.: 31

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.933

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.945

GnomAD2 exomes AF: 0.963 AC: 239336 AN: 248654 AF XY: 0.964

Gnomad AFR exome AF: 0.818

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.932

Gnomad EAS exome AF: 0.997

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.985

Gnomad OTH exome AF: 0.963

GnomAD4 exome AF: 0.978 AC: 1421424 AN: 1453848 Hom.: 695635 Cov.: 33 AF XY: 0.977 AC XY: 706735 AN XY: 723694

African (AFR) AF: 0.814 AC: 27160 AN: 33346

American (AMR) AF: 0.955 AC: 42649 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 24321 AN: 26048

East Asian (EAS) AF: 0.998 AC: 39395 AN: 39466

South Asian (SAS) AF: 0.934 AC: 80376 AN: 86048

European-Finnish (FIN) AF: 0.998 AC: 50322 AN: 50430

Middle Eastern (MID) AF: 0.926 AC: 5224 AN: 5640

European-Non Finnish (NFE) AF: 0.987 AC: 1093908 AN: 1108034

Other (OTH) AF: 0.965 AC: 58069 AN: 60164

GnomAD4 genome AF: 0.934 AC: 142184 AN: 152168 Hom.: 66838 Cov.: 31 AF XY: 0.936 AC XY: 69631 AN XY: 74390

African (AFR) AF: 0.822 AC: 34084 AN: 41486

American (AMR) AF: 0.943 AC: 14434 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3254 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5162 AN: 5178

South Asian (SAS) AF: 0.933 AC: 4502 AN: 4824

European-Finnish (FIN) AF: 0.999 AC: 10589 AN: 10602

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 66977 AN: 67990

Other (OTH) AF: 0.945 AC: 1996 AN: 2112

Alfa AF: 0.950 Hom.: 14474

Bravo AF: 0.927

Asia WGS AF: 0.954 AC: 3304 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Retinoblastoma (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.81
DANN	Benign	0.56
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs198617; hg19: chr13-48919358; COSMIC: COSV99922900;