13-48411623-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001162498.3(LPAR6):c.801A>C(p.Ala267=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,612,216 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (2 hom.)
• Consequence: LPAR6 NM_001162498.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.83

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-48411623-T-G is Benign according to our data. Variant chr13-48411623-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 780057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00141 (214/152294) while in subpopulation NFE AF= 0.00251 (171/68008). AF 95% confidence interval is 0.00221. There are 1 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPAR6	NM_001162498.3	c.801A>C	p.Ala267=	synonymous_variant	1/1	ENST00000620633.5
RB1	NM_000321.3	c.1695+30180T>G		intron_variant		ENST00000267163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPAR6	ENST00000620633.5	c.801A>C	p.Ala267=	synonymous_variant	1/1	5	NM_001162498.3	P1
RB1	ENST00000267163.6	c.1695+30180T>G		intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00138 AC: 344 AN: 250116 Hom.: 1 AF XY: 0.00149 AC XY: 201 AN XY: 135282

Gnomad AFR exome AF: 0.000558

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.00250 AC: 3647 AN: 1459922 Hom.: 2 Cov.: 31 AF XY: 0.00248 AC XY: 1799 AN XY: 726396

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00305

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74476

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00136

EpiCase AF: 0.00256

EpiControl AF: 0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	LPAR6: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.5
Dann	Benign	0.75

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: rs4151552; hg19: chr13-48985759; COSMIC: COSV57307467; COSMIC: COSV57307467;