13-48411839-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001162498.3(LPAR6):c.585T>C(p.Ile195=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,612,776 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (69 hom.)
• Consequence: LPAR6 NM_001162498.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.816

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 13-48411839-A-G is Benign according to our data. Variant chr13-48411839-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 769847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.816 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00555 (846/152304) while in subpopulation NFE AF= 0.00863 (587/68012). AF 95% confidence interval is 0.00805. There are 5 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPAR6	NM_001162498.3	c.585T>C	p.Ile195=	synonymous_variant	1/1	ENST00000620633.5
RB1	NM_000321.3	c.1695+30396A>G		intron_variant		ENST00000267163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPAR6	ENST00000620633.5	c.585T>C	p.Ile195=	synonymous_variant	1/1	5	NM_001162498.3	P1
RB1	ENST00000267163.6	c.1695+30396A>G		intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152186 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00863

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00632 AC: 1577 AN: 249524 Hom.: 6 AF XY: 0.00634 AC XY: 858 AN XY: 135226

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00591

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00314

Gnomad FIN exome AF: 0.00786

Gnomad NFE exome AF: 0.00873

Gnomad OTH exome AF: 0.00986

GnomAD4 exome AF: 0.00838 AC: 12241 AN: 1460472 Hom.: 69 Cov.: 32 AF XY: 0.00829 AC XY: 6024 AN XY: 726636

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00579

Gnomad4 ASJ exome AF: 0.00517

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00311

Gnomad4 FIN exome AF: 0.00803

Gnomad4 NFE exome AF: 0.00954

Gnomad4 OTH exome AF: 0.00701

GnomAD4 genome AF: 0.00555 AC: 846 AN: 152304 Hom.: 5 Cov.: 32 AF XY: 0.00546 AC XY: 407 AN XY: 74490

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.00863

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00411 Hom.: 1

Bravo AF: 0.00552

EpiCase AF: 0.00971

EpiControl AF: 0.00765

ClinVar

Significance: Benign/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	Apr 01, 2024	LPAR6: BP4, BP7, BS2; RB1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	9.2
Dann	Benign	0.80

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: rs2233573; hg19: chr13-48985975;