chr13-48411682-T-A

Variant names:

• chr13-48411682-T-A
• NM_001162498.3:c.742A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PP3 PP5_Moderate

The NM_001162498.3(LPAR6):​c.742A>T​(p.Asn248Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV003932428: Well-established functional studies show a deleterious effect (PS3 downgraded to supporting);".

• Frequency: Genomes: not found (cov: 32)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.27
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003932428: Well-established functional studies show a deleterious effect (PS3 downgraded to supporting)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789
• PP5: Variant 13-48411682-T-A is Pathogenic according to our data. Variant chr13-48411682-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2505340.Status of the report is criteria_provided_single_submitter, 1 stars.

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.742A>T	p.Asn248Tyr	missense	Exon 1 of 1	NP_001155970.1	P43657
	RB1	NM_000321.3	MANE Select	c.1695+30239T>A		intron	N/A	NP_000312.2	P06400
	LPAR6	NM_001162497.3		c.742A>T	p.Asn248Tyr	missense	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.742A>T	p.Asn248Tyr	missense	Exon 1 of 1	ENSP00000482660.1	P43657
	LPAR6	ENST00000378434.8	TSL:1	c.742A>T	p.Asn248Tyr	missense	Exon 7 of 7	ENSP00000367691.3	P43657
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.1695+30239T>A		intron	N/A	ENSP00000267163.4	P06400

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypotrichosis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.010	D
Sift4G	Benign	0.25	T
Polyphen		0.99	D
Vest4		0.54
MutPred		0.82		Gain of catalytic residue at I247 (P = 0.0625)
MVP		0.81
MPC		0.34
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.61
gMVP		0.72
Mutation Taster		=20/80	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

hg19: chr13-48985818;