rs3092895

Variant names:

• chr13-48453004-A-G
• rs3092895
• NM_000321.3:c.1707A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-48453004-A-G
• chr13-48453004-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000321.3(RB1):​c.1707A>G​(p.Leu569Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,612,770 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (5 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.779
• Publications: 5 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 13-48453004-A-G is Benign according to our data. Variant chr13-48453004-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.779 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00054 (788/1460502) while in subpopulation SAS AF = 0.00224 (193/86246). AF 95% confidence interval is 0.00198. There are 5 homozygotes in GnomAdExome4. There are 445 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 84 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.1707A>G	p.Leu569Leu	synonymous	Exon 18 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.1707A>G	p.Leu569Leu	synonymous	Exon 18 of 27	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1707A>G	p.Leu569Leu	synonymous	Exon 18 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.*1075A>G		non_coding_transcript_exon	Exon 13 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000467505.6	TSL:1	n.*1075A>G		3_prime_UTR	Exon 13 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000638 AC: 160 AN: 250660 AF XY: 0.000671

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000756

Gnomad NFE exome AF: 0.000775

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000540 AC: 788 AN: 1460502 Hom.: 5 Cov.: 31 AF XY: 0.000612 AC XY: 445 AN XY: 726594

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39608

South Asian (SAS) AF: 0.00224 AC: 193 AN: 86246

European-Finnish (FIN) AF: 0.000967 AC: 51 AN: 52762

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.000444 AC: 494 AN: 1111532

Other (OTH) AF: 0.000630 AC: 38 AN: 60364

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74470

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.000332

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Retinoblastoma (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.6
DANN	Benign	0.66
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3092895; hg19: chr13-49027140;