rs187110786

Variant names:

• chr13-48342724-C-G
• rs187110786
• NM_000321.3:c.380+10C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-48342724-C-G
• chr13-48342724-C-A
• chr13-48342724-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000321.3(RB1):​c.380+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,551,550 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.260
• 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: 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 13-48342724-C-G is Benign according to our data. Variant chr13-48342724-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00153 (233/152100) while in subpopulation NFE AF = 0.00228 (155/67882). AF 95% confidence interval is 0.00199. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 233 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.380+10C>G		intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.380+10C>G		intron	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.380+10C>G		intron	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.380+10C>G		intron	N/A	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.138-17293C>G		intron	N/A	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.380+10C>G		intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00175 AC: 438 AN: 250100 AF XY: 0.00173

Gnomad AFR exome AF: 0.000562

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00221 AC: 3096 AN: 1399450 Hom.: 4 Cov.: 24 AF XY: 0.00219 AC XY: 1534 AN XY: 699650

African (AFR) AF: 0.000467 AC: 15 AN: 32142

American (AMR) AF: 0.000606 AC: 27 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 33 AN: 25722

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39280

South Asian (SAS) AF: 0.00125 AC: 106 AN: 84888

European-Finnish (FIN) AF: 0.00237 AC: 126 AN: 53166

Middle Eastern (MID) AF: 0.000356 AC: 2 AN: 5622

European-Non Finnish (NFE) AF: 0.00254 AC: 2682 AN: 1055806

Other (OTH) AF: 0.00179 AC: 104 AN: 58258

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74360

African (AFR) AF: 0.000433 AC: 18 AN: 41542

American (AMR) AF: 0.000851 AC: 13 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 67882

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00139

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Retinoblastoma (5)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	RB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.54
PhyloP100		-0.26
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs187110786; hg19: chr13-48916860; COSMIC: COSV57335296;