13-48411798-T-G

Variant names:

• chr13-48411798-T-G
• rs750617332
• NM_001162498.3:c.626A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001162498.3(LPAR6):​c.626A>C​(p.Lys209Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20718354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPAR6	NM_001162498.3	c.626A>C	p.Lys209Thr	missense_variant	Exon 1 of 1	ENST00000620633.5	NP_001155970.1
RB1	NM_000321.3	c.1695+30355T>G		intron_variant	Intron 17 of 26	ENST00000267163.6	NP_000312.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPAR6	ENST00000620633.5	c.626A>C	p.Lys209Thr	missense_variant	Exon 1 of 1	5	NM_001162498.3	ENSP00000482660.1
RB1	ENST00000267163.6	c.1695+30355T>G		intron_variant	Intron 17 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460560 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726702

Gnomad4 AFR exome AF: 0.0000599

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: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	.;D;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.065
Sift	Benign	0.11	T;.;T
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.048	B;B;B
Vest4		0.19
MutPred		0.72		Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);Loss of MoRF binding (P = 0.0477);
MVP		0.48
MPC		0.079
ClinPred		0.30	T
GERP RS		2.8
Varity_R		0.15
gMVP		0.52

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: rs750617332; hg19: chr13-48985934;