13-48411594-A-G

Position:

• chr13-48411594-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001162498.3(LPAR6):​c.830T>C​(p.Leu277Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 13-48411594-A-G is Pathogenic according to our data. Variant chr13-48411594-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2505341.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPAR6	NM_001162498.3	c.830T>C	p.Leu277Pro	missense_variant	1/1	ENST00000620633.5
RB1	NM_000321.3	c.1695+30151A>G		intron_variant		ENST00000267163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPAR6	ENST00000620633.5	c.830T>C	p.Leu277Pro	missense_variant	1/1	5	NM_001162498.3	P1
RB1	ENST00000267163.6	c.1695+30151A>G		intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypotrichosis 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

-

This variant is interpreted as likely pathogenic for Hypotrichosis 8, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 upgraded to strong); For recessive disorders, detected in trans with a pathogenic variant (PM3 downgraded to supporting); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.6	D;.;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.88		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.70
MPC		0.41
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48985730;