13-48409927-G-A

Variant names:

• chr13-48409927-G-A
• rs198604
• NM_000321.3:c.1695+28484G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000267163.6(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 ENST00000267163.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200
• Publications: 11 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]

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]

LPAR6 Gene-Disease associations (from GenCC):

• hypotrichosis 8

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• hypotrichosis simplex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated familial wooly hair disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000267163.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.1695+28484G>A		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.1695+28484G>A		intron	N/A	NP_001394094.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1695+28484G>A		intron	N/A	ENSP00000267163.4
	LPAR6	ENST00000465365.6	TSL:1	n.1069-1160C>T		intron	N/A
	RB1	ENST00000467505.6	TSL:1	n.*1063+28484G>A		intron	N/A	ENSP00000434702.1

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

African (AFR) AF: 0.0931 AC: 3860 AN: 41472

American (AMR) AF: 0.173 AC: 2649 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3464

East Asian (EAS) AF: 0.226 AC: 1170 AN: 5172

South Asian (SAS) AF: 0.258 AC: 1244 AN: 4818

European-Finnish (FIN) AF: 0.256 AC: 2699 AN: 10534

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16367 AN: 67954

Other (OTH) AF: 0.188 AC: 395 AN: 2102

Alfa AF: 0.222 Hom.: 10152

Bravo AF: 0.184

Asia WGS AF: 0.232 AC: 806 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.0
DANN	Benign	0.90
PhyloP100		0.0020
Mutation Taster		=100/0	polymorphism (auto)

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: rs198604; hg19: chr13-48984063;