13-48342607-T-C

Variant names:

• chr13-48342607-T-C
• rs750136284
• NM_000321.3:c.273T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000321.3(RB1):​c.273T>C​(p.Tyr91Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,594,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.41
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 13-48342607-T-C is Benign according to our data. Variant chr13-48342607-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458160.
• BS2: High AC in GnomAdExome4 at 59 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.273T>C	p.Tyr91Tyr	synonymous	Exon 3 of 27	NP_000312.2
	RB1	NM_001407165.1		c.273T>C	p.Tyr91Tyr	synonymous	Exon 3 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.273T>C	p.Tyr91Tyr	synonymous	Exon 3 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.273T>C	p.Tyr91Tyr	synonymous	Exon 3 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.138-17410T>C		intron	N/A	ENSP00000434702.1
	RB1	ENST00000924352.1		c.273T>C	p.Tyr91Tyr	synonymous	Exon 3 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152050 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250816 AF XY: 0.0000221

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000409 AC: 59 AN: 1442292 Hom.: 0 Cov.: 28 AF XY: 0.0000362 AC XY: 26 AN XY: 718590

African (AFR) AF: 0.00 AC: 0 AN: 33016

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.0000512 AC: 56 AN: 1094670

Other (OTH) AF: 0.0000502 AC: 3 AN: 59704

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.8
DANN	Benign	0.49
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs750136284; hg19: chr13-48916743;