13-48411491-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001162498.3(LPAR6):c.933A>T(p.Arg311Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 6.8e-7 (0 hom.)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.583

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0583179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPAR6	NM_001162498.3	c.933A>T	p.Arg311Ser	missense_variant	1/1	ENST00000620633.5
RB1	NM_000321.3	c.1695+30048T>A		intron_variant		ENST00000267163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPAR6	ENST00000620633.5	c.933A>T	p.Arg311Ser	missense_variant	1/1	5	NM_001162498.3	P1
RB1	ENST00000267163.6	c.1695+30048T>A		intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460522 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.933A>T (p.R311S) alteration is located in exon 7 (coding exon 1) of the LPAR6 gene. This alteration results from a A to T substitution at nucleotide position 933, causing the arginine (R) at amino acid position 311 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	15
Dann	Benign	0.82
DEOGEN2	Benign	0.027	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.55	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.078
Sift	Benign	0.096	T;.;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.090
MutPred		0.47		Loss of MoRF binding (P = 0.0277);Loss of MoRF binding (P = 0.0277);Loss of MoRF binding (P = 0.0277);
MVP		0.23
MPC		0.055
ClinPred		0.088	T
GERP RS		0.58
Varity_R		0.10
gMVP		0.41

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: rs1948800044; hg19: chr13-48985627;