NM_001162498.3:c.587C>A

Variant names:

• chr13-48411837-G-T
• rs115596308
• NM_001162498.3:c.587C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001162498.3(LPAR6):​c.587C>A​(p.Pro196His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P196L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00
• Publications: 11 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-48411837-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30780.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

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.587C>A	p.Pro196His	missense	Exon 1 of 1	NP_001155970.1
	RB1	NM_000321.3	MANE Select	c.1695+30394G>T		intron	N/A	NP_000312.2
	LPAR6	NM_001162497.3		c.587C>A	p.Pro196His	missense	Exon 5 of 5	NP_001155969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPAR6	ENST00000620633.5	TSL:5 MANE Select	c.587C>A	p.Pro196His	missense	Exon 1 of 1	ENSP00000482660.1
	LPAR6	ENST00000378434.8	TSL:1	c.587C>A	p.Pro196His	missense	Exon 7 of 7	ENSP00000367691.3
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1695+30394G>T		intron	N/A	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249518 AF XY: 0.00000739

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.89		Gain of helix (P = 0.132)
MVP		0.81
MPC		0.36
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.91
Mutation Taster		=17/83	disease causing

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: rs115596308; hg19: chr13-48985973;