13-48411839-A-G

Variant names:

• chr13-48411839-A-G
• rs2233573
• NM_001162498.3:c.585T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.816
• Publications: 5 publications found

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]

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

ACMG classification

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

Sel.	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

Sel.	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.: 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

GnomAD2 exomes AF: 0.00632 AC: 1577 AN: 249524 AF XY: 0.00634

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.: 69 Cov.: 32 AF XY: 0.00829 AC XY: 6024 AN XY: 726636

African (AFR) AF: 0.00158 AC: 53 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: 0 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: 76 AN: 5768

European-Non Finnish (NFE) AF: 0.00954 AC: 10598 AN: 1110758

Other (OTH) AF: 0.00701 AC: 423 AN: 60366

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

African (AFR) AF: 0.00144 AC: 60 AN: 41564

American (AMR) AF: 0.00588 AC: 90 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00863 AC: 587 AN: 68012

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00273 Hom.: 1

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

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	LPAR6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.2
DANN	Benign	0.80
PhyloP100		0.82
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs2233573; hg19: chr13-48985975;