chr13-48411503-C-A

Position:

chr13-48411503-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001162498.3(LPAR6):c.921G>T(p.Trp307Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,612,538 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 8 hom., cov: 32)

Exomes 𝑓: 0.012 ( 109 hom. )

Consequence

LPAR6
NM_001162498.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.29

Variant links:

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]

LPAR6 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00554204).

BP6

Variant 13-48411503-C-A is Benign according to our data. Variant chr13-48411503-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 774331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00826 (1258/152222) while in subpopulation NFE AF= 0.0125 (847/67988). AF 95% confidence interval is 0.0118. There are 8 homozygotes in gnomad4. There are 624 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPAR6	NM_001162498.3 linkuse as main transcript	c.921G>T	p.Trp307Cys	missense_variant	1/1	ENST00000620633.5
RB1	NM_000321.3 linkuse as main transcript	c.1695+30060C>A		intron_variant		ENST00000267163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPAR6	ENST00000620633.5 linkuse as main transcript	c.921G>T	p.Trp307Cys	missense_variant	1/1	5	NM_001162498.3	P1
RB1	ENST00000267163.6 linkuse as main transcript	c.1695+30060C>A		intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00828

AC:

1259

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0125

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00875

AC:

2179

AN:

249030

Hom.:

AF XY:

0.00870

AC XY:

1172

AN XY:

134644

show subpopulations

Gnomad AFR exome

AF:

0.00316

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.000600

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00427

Gnomad FIN exome

AF:

0.0205

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0124

AC:

18063

AN:

1460316

Hom.:

109

Cov.:

AF XY:

0.0122

AC XY:

8828

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.00219

Gnomad4 AMR exome

AF:

0.00218

Gnomad4 ASJ exome

AF:

0.000767

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00524

Gnomad4 FIN exome

AF:

0.0207

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.00826

AC:

1258

AN:

152222

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

624

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00747

Gnomad4 FIN

AF:

0.0183

Gnomad4 NFE

AF:

0.0125

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00649

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0138

AC:

119

ExAC

AF:

0.00920

AC:

1117

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0112

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LPAR6: BP4, BS1, BS2; RB1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Retinoblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Benign

0.0075

T;T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

.;T;.

MetaRNN

Benign

0.0055

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

0.51

N;.;N

REVEL

Benign

0.14

Sift

Benign

0.048

D;.;D

Sift4G

Benign

0.17

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.33

MutPred

0.18

Loss of MoRF binding (P = 0.038);Loss of MoRF binding (P = 0.038);Loss of MoRF binding (P = 0.038);

MVP

0.82

MPC

0.18

ClinPred

0.085

GERP RS

5.7

Varity_R

0.15

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over