chr13-48380178-GACA-G

Variant names:

• chr13-48380178-GACA-G
• rs587776788
• NM_000321.3:c.1439_1441delACA

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000321.3(RB1):​c.1439_1441delACA​(p.Asn480del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000835651: Experimental studies have shown that this variant affects RB1 function (PMID:9342358, 10486322)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RB1 NM_000321.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.31
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000835651: Experimental studies have shown that this variant affects RB1 function (PMID: 9342358, 10486322).; SCV000580775: Functional studies have shown this variant to have a deleterious impact on protein function (Otterson GA et al. Am J Hum Genet, 1999 Oct;65(4):1040-6; Park Y et al. Cell Cycle, 2008 Aug;7(15):2384-91).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 24 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000321.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 13-48380178-GACA-G is Pathogenic according to our data. Variant chr13-48380178-GACA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 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.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*807_*809delACA		non_coding_transcript_exon	Exon 11 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*807_*809delACA		3_prime_UTR	Exon 11 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Retinoblastoma (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587776788; hg19: chr13-48954314; COSMIC: COSV57334482;