13-48348987-C-T

Variant names:

• chr13-48348987-C-T
• rs538578527
• NM_000321.3:c.571C>T
• RB1 p.Leu191Leu

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000321.3(RB1):​c.571C>T​(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,600,044 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.29
• 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 13-48348987-C-T is Benign according to our data. Variant chr13-48348987-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 458173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000145 (22/151332) while in subpopulation SAS AF = 0.00438 (21/4796). AF 95% confidence interval is 0.00293. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.571C>T	p.Leu191Leu	synonymous	Exon 6 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.571C>T	p.Leu191Leu	synonymous	Exon 6 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.571C>T	p.Leu191Leu	synonymous	Exon 6 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.571C>T	p.Leu191Leu	synonymous	Exon 6 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.138-11030C>T		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.694C>T	p.Leu232Leu	synonymous	Exon 7 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 151216 Hom.: 0 Cov.: 32

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: 0.00416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 51 AN: 248654 AF XY: 0.000304

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 230 AN: 1448712 Hom.: 3 Cov.: 30 AF XY: 0.000225 AC XY: 162 AN XY: 720672

African (AFR) AF: 0.00 AC: 0 AN: 33170

American (AMR) AF: 0.00 AC: 0 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 39234

South Asian (SAS) AF: 0.00256 AC: 218 AN: 85152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1104158

Other (OTH) AF: 0.000151 AC: 9 AN: 59726

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151332 Hom.: 0 Cov.: 32 AF XY: 0.000217 AC XY: 16 AN XY: 73888

African (AFR) AF: 0.00 AC: 0 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00438 AC: 21 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67634

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.00116 AC: 4 AN: 3458

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Retinoblastoma (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		1.3
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs538578527;

hg19: chr13-48923123;