Genetic Variant NM_001162498.3:c.585T>C (chr13-48411839-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001162498.3(LPAR6):c.585T>C(p.Ile195Ile) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.816

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001162498.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPAR6	NM_001162498.3	MANE Select	c.585T>C	p.Ile195Ile	synonymous	Exon 1 of 1	NP_001155970.1	P43657
RB1	NM_000321.3	MANE Select	c.1695+30396A>G		intron	N/A	NP_000312.2	P06400
LPAR6	NM_001162497.3		c.585T>C	p.Ile195Ile	synonymous	Exon 5 of 5	NP_001155969.1	P43657

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPAR6	ENST00000620633.5	TSL:5 MANE Select	c.585T>C	p.Ile195Ile	synonymous	Exon 1 of 1	ENSP00000482660.1	P43657
LPAR6	ENST00000378434.8	TSL:1	c.585T>C	p.Ile195Ile	synonymous	Exon 7 of 7	ENSP00000367691.3	P43657
RB1	ENST00000267163.6	TSL:1 MANE Select	c.1695+30396A>G		intron	N/A	ENSP00000267163.4	P06400

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152186

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00632

AC:

1577

AN:

249524

AF XY:

0.00634

show subpopulations

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 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.:

Cov.:

AF XY:

0.00829

AC XY:

6024

AN XY:

726636

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33448

American (AMR)

AF:

0.00579

AC:

259

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00517

AC:

135

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00311

AC:

268

AN:

86230

European-Finnish (FIN)

AF:

0.00803

AC:

429

AN:

53402

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00954

AC:

10598

AN:

1110758

Other (OTH)

AF:

0.00701

AC:

423

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

686

1371

2057

2742

3428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00555

AC:

846

AN:

152304

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

407

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41564

American (AMR)

AF:

0.00588

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00527

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00863

AC:

587

AN:

68012

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.00552

EpiCase

AF:

0.00971

EpiControl

AF:

0.00765

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

LPAR6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.2

(source)

DANN

Benign

0.80

PhyloP100

0.82

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over