4-3514898-CGA-C

Position:

• chr4-3514898-CGA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002337.4(LRPAP1):​c.863_864del​(p.Ile288ArgfsTer118) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: LRPAP1 NM_002337.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.196 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-3514898-CGA-C is Pathogenic according to our data. Variant chr4-3514898-CGA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65461.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRPAP1	NM_002337.4	c.863_864del	p.Ile288ArgfsTer118	frameshift_variant	7/8	ENST00000650182.1	NP_002328.1
LRPAP1	NR_110005.2	n.826_827del		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRPAP1	ENST00000650182.1	c.863_864del	p.Ile288ArgfsTer118	frameshift_variant	7/8		NM_002337.4	ENSP00000497444	P1
LRPAP1	ENST00000296325.9	n.826_827del		non_coding_transcript_exon_variant	7/8	1
LRPAP1	ENST00000648517.1	c.*355_*356del		3_prime_UTR_variant, NMD_transcript_variant	8/8			ENSP00000496947

Frequencies

GnomAD3 genomes Cov.: 35

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 35

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopia 23, autosomal recessive Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122836; hg19: chr4-3516625;