13-48411482-G-C

Variant names:

• chr13-48411482-G-C
• rs1948799851
• NM_001162498.3:c.942C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001162498.3(LPAR6):​c.942C>G​(p.Phe314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.568
• Publications: 0 publications found

Genes affected

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]

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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03121519).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001162498.3. 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
	LPAR6	NM_001162498.3	MANE Select	c.942C>G	p.Phe314Leu	missense	Exon 1 of 1	NP_001155970.1	P43657
	RB1	NM_000321.3	MANE Select	c.1695+30039G>C		intron	N/A	NP_000312.2	P06400
	LPAR6	NM_001162497.3		c.942C>G	p.Phe314Leu	missense	Exon 5 of 5	NP_001155969.1	P43657

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPAR6	ENST00000620633.5	TSL:5 MANE Select	c.942C>G	p.Phe314Leu	missense	Exon 1 of 1	ENSP00000482660.1	P43657
	LPAR6	ENST00000378434.8	TSL:1	c.942C>G	p.Phe314Leu	missense	Exon 7 of 7	ENSP00000367691.3	P43657
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1695+30039G>C		intron	N/A	ENSP00000267163.4	P06400

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460520 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726582

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111156

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.66
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.57
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.029
Sift	Benign	0.51	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.25		Gain of MoRF binding (P = 0.1275)
MVP		0.33
MPC		0.057
ClinPred		0.070	T
GERP RS		3.1
Varity_R		0.070
gMVP		0.26
Mutation Taster		=91/9	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: rs1948799851; hg19: chr13-48985618;