4-3512969-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002337.4(LRPAP1):c.*5A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,609,468 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: LRPAP1 NM_002337.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.01

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-3512969-T-C is Benign according to our data. Variant chr4-3512969-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3041339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRPAP1	NM_002337.4	c.*5A>G		3_prime_UTR_variant	8/8	ENST00000650182.1
LRPAP1	NR_110005.2	n.1042A>G		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPAP1	ENST00000650182.1	c.*5A>G		3_prime_UTR_variant	8/8		NM_002337.4	P1
LRPAP1	ENST00000296325.9	n.1042A>G		non_coding_transcript_exon_variant	8/8	1

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 548 AN: 152236 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00394 AC: 952 AN: 241514 Hom.: 6 AF XY: 0.00383 AC XY: 501 AN XY: 130824

Gnomad AFR exome AF: 0.000913

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000241

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00671

GnomAD4 exome AF: 0.00494 AC: 7202 AN: 1457114 Hom.: 27 Cov.: 32 AF XY: 0.00493 AC XY: 3568 AN XY: 724366

Gnomad4 AFR exome AF: 0.000779

Gnomad4 AMR exome AF: 0.00354

Gnomad4 ASJ exome AF: 0.000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000318

Gnomad4 FIN exome AF: 0.00294

Gnomad4 NFE exome AF: 0.00594

Gnomad4 OTH exome AF: 0.00389

GnomAD4 genome AF: 0.00359 AC: 547 AN: 152354 Hom.: 2 Cov.: 34 AF XY: 0.00325 AC XY: 242 AN XY: 74510

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00629

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00488 Hom.: 1

Bravo AF: 0.00336

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LRPAP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.082
Dann	Benign	0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs148120809; hg19: chr4-3514696;