13-48411623-T-G

Variant names:

• chr13-48411623-T-G
• rs4151552
• NM_001162498.3:c.801A>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.801A>C​(p.Ala267Ala) 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
• Publications: 2 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=-0.82).
• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.801A>C	p.Ala267Ala	synonymous	Exon 1 of 1	NP_001155970.1	P43657
	RB1	NM_000321.3	MANE Select	c.1695+30180T>G		intron	N/A	NP_000312.2	P06400
	LPAR6	NM_001162497.3		c.801A>C	p.Ala267Ala	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.801A>C	p.Ala267Ala	synonymous	Exon 1 of 1	ENSP00000482660.1	P43657
	LPAR6	ENST00000378434.8	TSL:1	c.801A>C	p.Ala267Ala	synonymous	Exon 7 of 7	ENSP00000367691.3	P43657
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1695+30180T>G		intron	N/A	ENSP00000267163.4	P06400

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

GnomAD2 exomes AF: 0.00138 AC: 344 AN: 250116 AF XY: 0.00149

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 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

African (AFR) AF: 0.000509 AC: 17 AN: 33412

American (AMR) AF: 0.000403 AC: 18 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.000986 AC: 85 AN: 86200

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53362

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00305 AC: 3385 AN: 1110408

Other (OTH) AF: 0.00179 AC: 108 AN: 60332

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

African (AFR) AF: 0.000553 AC: 23 AN: 41572

American (AMR) AF: 0.000720 AC: 11 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00136

EpiCase AF: 0.00256

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.75
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs4151552; hg19: chr13-48985759; COSMIC: COSV57307467; COSMIC: COSV57307467;