rs773243225

chr4-3532232-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002337.4(LRPAP1):c.181C>T(p.Gln61Ter) 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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.58

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 Pathogenic. Variant got 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 id is 505006.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRPAP1	NM_002337.4	c.181C>T	p.Gln61Ter	stop_gained	1/8	ENST00000650182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPAP1	ENST00000650182.1	c.181C>T	p.Gln61Ter	stop_gained	1/8		NM_002337.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000640 AC: 1 AN: 156204 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82388

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 SAS 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: 1 AN: 1398568 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000205 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare isolated myopia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2016

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	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.68	D
MutationTaster	Benign	1.0	A
Vest4		0.71
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs773243225; hg19: chr4-3533959;