rs398122836

Variant names:

• chr4-3514898-CGA-C
• rs398122836
• NM_002337.4:c.863_864delTC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002337.4(LRPAP1):​c.863_864delTC​(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 (★). Variant results in nonsense mediated mRNA decay.

• 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
• Publications: 4 publications found

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

ACMG classification

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 4-3514898-CGA-C is Pathogenic according to our data. Variant chr4-3514898-CGA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 65461.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	c.863_864delTC	p.Ile288ArgfsTer118	frameshift_variant	Exon 7 of 8	ENST00000650182.1	NP_002328.1
LRPAP1	NR_110005.2	n.826_827delTC		non_coding_transcript_exon_variant	Exon 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRPAP1	ENST00000650182.1	c.863_864delTC	p.Ile288ArgfsTer118	frameshift_variant	Exon 7 of 8		NM_002337.4	ENSP00000497444.1
LRPAP1	ENST00000296325.9	n.826_827delTC		non_coding_transcript_exon_variant	Exon 7 of 8	1
LRPAP1	ENST00000648517.1	n.*355_*356delTC		non_coding_transcript_exon_variant	Exon 8 of 8			ENSP00000496947.1
LRPAP1	ENST00000648517.1	n.*355_*356delTC		3_prime_UTR_variant	Exon 8 of 8			ENSP00000496947.1

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

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122836; hg19: chr4-3516625;