rs773243225

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_002337.4(LRPAP1):c.181C>T(p.Gln61*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000715 in 1,398,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

LRPAP1
NM_002337.4 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.58

Publications

2 publications found

Variant links:

Genes affected

LRPAP1 (HGNC:6701): (LDL receptor related protein associated protein 1) This gene encodes a protein that interacts with the low density lipoprotein (LDL) receptor-related protein and facilitates its proper folding and localization by preventing the binding of ligands. Mutations in this gene have been identified in individuals with myopia 23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

LRPAP1 Gene-Disease associations (from GenCC):

myopia 23, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

LRPAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-3532232-G-A is Pathogenic according to our data. Variant chr4-3532232-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 505006.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRPAP1	NM_002337.4 link	c.181C>T	p.Gln61*	stop_gained	Exon 1 of 8	ENST00000650182.1	NP_002328.1	P30533
LRPAP1	NR_110005.2 link	n.-83C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRPAP1	ENST00000650182.1 link	c.181C>T	p.Gln61*	stop_gained	Exon 1 of 8		NM_002337.4	ENSP00000497444.1		P30533

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000640

AC:

AN:

156204

AF XY:

0.0000121

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000226

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398568

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31620

American (AMR)

AF:

0.0000280

AC:

AN:

35744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25166

East Asian (EAS)

AF:

0.00

AC:

AN:

35776

South Asian (SAS)

AF:

0.00

AC:

AN:

79302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078888

Other (OTH)

AF:

0.00

AC:

AN:

57968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000205

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rare isolated myopia

Pathogenic:1

May 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gln61X variant in LRPAP1 has not been previously reported in the literatur e and data from large population studies is insufficient to assess the frequency of this variant. This nonsense variant leads to a premature termination codon a t position 61, which is predicted to lead to a truncated or absent protein. Bial lelic loss of function of the LRPAP1 gene has been reported in 8 families with n on-syndromic myopia (Aldahmesh 2013, Jiang 2015, Khan 2016). In summary, althoug h additional studies are required to fully establish its clinical significance, the p.Gln61X variant is likely pathogenic for myopia in an autosomal recessive m anner based on its predicted functional impact. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.68

PhyloP100

4.6

Vest4

0.71

GERP RS

2.9

PromoterAI

0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=6/194

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over