rs578226820

Variant names:

• chr13-48380073-T-C
• rs578226820
• NM_000321.3:c.1410T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-48380073-T-C
• chr13-48380073-T-G
• chr13-48380073-T-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000321.3(RB1):​c.1410T>C​(p.Ile470Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,386,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000065 (1 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.18
• Publications: 4 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

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 13-48380073-T-C is Benign according to our data. Variant chr13-48380073-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BS2: High AC in GnomAd4 at 18 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.1410T>C	p.Ile470Ile	synonymous	Exon 15 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1410T>C	p.Ile470Ile	synonymous	Exon 15 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.1410T>C	p.Ile470Ile	synonymous	Exon 15 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.1410T>C	p.Ile470Ile	synonymous	Exon 15 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*778T>C		non_coding_transcript_exon	Exon 10 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*778T>C		3_prime_UTR	Exon 10 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes AF: 0.000120 AC: 18 AN: 150578 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000991

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: 0.000483

GnomAD2 exomes AF: 0.000171 AC: 23 AN: 134210 AF XY: 0.000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000571

GnomAD4 exome AF: 0.0000647 AC: 80 AN: 1236002 Hom.: 1 Cov.: 22 AF XY: 0.0000601 AC XY: 37 AN XY: 615652

African (AFR) AF: 0.00 AC: 0 AN: 26632

American (AMR) AF: 0.000952 AC: 26 AN: 27306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22676

East Asian (EAS) AF: 0.00 AC: 0 AN: 34104

South Asian (SAS) AF: 0.0000149 AC: 1 AN: 67262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45550

Middle Eastern (MID) AF: 0.000281 AC: 1 AN: 3564

European-Non Finnish (NFE) AF: 0.0000449 AC: 43 AN: 957374

Other (OTH) AF: 0.000175 AC: 9 AN: 51534

GnomAD4 genome AF: 0.000119 AC: 18 AN: 150674 Hom.: 0 Cov.: 30 AF XY: 0.0000951 AC XY: 7 AN XY: 73610

African (AFR) AF: 0.00 AC: 0 AN: 41308

American (AMR) AF: 0.000990 AC: 15 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67678

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Retinoblastoma (2)
-	-	1	RB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		1.2
Mutation Taster		=98/2	polymorphism

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: rs578226820; hg19: chr13-48954209;