rs198604

Positions:

• chr13-48409927-G-A
• chr13-48409927-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000321.3(RB1):​c.1695+28484G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 151,990 control chromosomes in the GnomAD database, including 3,198 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3198 hom., cov: 31)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200

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]

LPAR6 (HGNC:15520): (lysophosphatidic acid receptor 6) The protein encoded by this gene belongs to the family of G-protein coupled receptors, that are preferentially activated by adenosine and uridine nucleotides. This gene aligns with an internal intron of the retinoblastoma susceptibility gene in the reverse orientation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1695+28484G>A		intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.1695+28484G>A		intron_variant
LPAR6	XM_047430023.1	c.192+5773C>T		intron_variant
LPAR6	XM_047430024.1	c.120+5773C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1695+28484G>A		intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29433 AN: 151872 Hom.: 3202 Cov.: 31

Gnomad AFR AF: 0.0933

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.191

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

GnomAD4 genome AF: 0.194 AC: 29426 AN: 151990 Hom.: 3198 Cov.: 31 AF XY: 0.197 AC XY: 14613 AN XY: 74292

Gnomad4 AFR AF: 0.0931

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.188

Alfa AF: 0.228 Hom.: 6803

Bravo AF: 0.184

Asia WGS AF: 0.232 AC: 806 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.0
DANN	Benign	0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs198604; hg19: chr13-48984063;