chr13-48438357-G-A

Variant names:

• chr13-48438357-G-A
• rs425834
• NM_000321.3:c.1696-14636G>A

Variant summary

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

The NM_000321.3(RB1):​c.1696-14636G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 151,964 control chromosomes in the GnomAD database, including 52,226 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 0.78 (52226 hom., cov: 30)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.623
• Publications: 6 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.1696-14636G>A		intron	N/A	NP_000312.2
	RB1	NM_001407165.1		c.1696-14636G>A		intron	N/A	NP_001394094.1
	LPAR6	NM_005767.7		c.-1474+6196C>T		intron	N/A	NP_005758.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1696-14636G>A		intron	N/A	ENSP00000267163.4
	LPAR6	ENST00000378434.8	TSL:1	c.-1474+6196C>T		intron	N/A	ENSP00000367691.3
	LPAR6	ENST00000465365.6	TSL:1	n.319+1252C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.783 AC: 118927 AN: 151846 Hom.: 52234 Cov.: 30

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.816

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

GnomAD4 genome AF: 0.783 AC: 118927 AN: 151964 Hom.: 52226 Cov.: 30 AF XY: 0.788 AC XY: 58537 AN XY: 74288

African (AFR) AF: 0.347 AC: 14331 AN: 41340

American (AMR) AF: 0.879 AC: 13417 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 3192 AN: 3472

East Asian (EAS) AF: 0.862 AC: 4447 AN: 5160

South Asian (SAS) AF: 0.905 AC: 4348 AN: 4806

European-Finnish (FIN) AF: 0.974 AC: 10319 AN: 10594

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 65998 AN: 67998

Other (OTH) AF: 0.810 AC: 1714 AN: 2116

Alfa AF: 0.842 Hom.: 7230

Bravo AF: 0.756

Asia WGS AF: 0.815 AC: 2835 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.50
PhyloP100		0.62
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: rs425834; hg19: chr13-49012493; COSMIC: COSV57303517;