rs773243225

Variant names:

• chr4-3532232-G-A
• rs773243225
• NM_002337.4:c.181C>T

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.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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.58
• Publications: 2 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 4-3532232-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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002337.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPAP1	NM_002337.4	MANE Select	c.181C>T	p.Gln61*	stop_gained	Exon 1 of 8	NP_002328.1
	LRPAP1	NR_110005.2		n.-83C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPAP1	ENST00000650182.1	MANE Select	c.181C>T	p.Gln61*	stop_gained	Exon 1 of 8	ENSP00000497444.1
	LRPAP1	ENST00000931150.1		c.181C>T	p.Gln61*	stop_gained	Exon 1 of 9	ENSP00000601209.1
	LRPAP1	ENST00000897675.1		c.181C>T	p.Gln61*	stop_gained	Exon 1 of 8	ENSP00000567734.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000640 AC: 1 AN: 156204 AF XY: 0.0000121

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

African (AFR) AF: 0.00 AC: 0 AN: 31620

American (AMR) AF: 0.0000280 AC: 1 AN: 35744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35776

South Asian (SAS) AF: 0.00 AC: 0 AN: 79302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078888

Other (OTH) AF: 0.00 AC: 0 AN: 57968

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000205 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare isolated myopia (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.6
Vest4		0.71
GERP RS		2.9
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs773243225; hg19: chr4-3533959;