4-3516145-G-A

Position:

chr4-3516145-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002337.4(LRPAP1):c.805C>T(p.Leu269Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,582,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

LRPAP1
NM_002337.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.35

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04671046).

BP6

Variant 4-3516145-G-A is Benign according to our data. Variant chr4-3516145-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3120352.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 linkuse as main transcript	c.805C>T	p.Leu269Phe	missense_variant	6/8	ENST00000650182.1	NP_002328.1
LRPAP1	NR_110005.2 linkuse as main transcript	n.768C>T		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LRPAP1	ENST00000650182.1 linkuse as main transcript	c.805C>T	p.Leu269Phe	missense_variant	6/8		NM_002337.4	ENSP00000497444	P1
LRPAP1	ENST00000296325.9 linkuse as main transcript	n.768C>T		non_coding_transcript_exon_variant	6/8	1
LRPAP1	ENST00000515119.5 linkuse as main transcript	c.*582C>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	2		ENSP00000421648
LRPAP1	ENST00000648517.1 linkuse as main transcript	c.*297C>T		3_prime_UTR_variant, NMD_transcript_variant	7/8			ENSP00000496947

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000150

AC:

AN:

199560

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

106764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000140

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000581

Gnomad NFE exome

AF:

0.000276

Gnomad OTH exome

AF:

0.000196

GnomAD4 exome

AF:

0.000236

AC:

338

AN:

1430040

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

158

AN XY:

708102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.000127

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000792

Gnomad4 NFE exome

AF:

0.000276

Gnomad4 OTH exome

AF:

0.000405

GnomAD4 genome

AF:

0.000112

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.0000670

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.1

DANN

Benign

0.076

DEOGEN2

Benign

0.093

T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.79

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.93

N;N

MutationTaster

Benign

0.78

PrimateAI

Benign

0.41

PROVEAN

Benign

4.0

N;.

REVEL

Benign

0.081

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Polyphen

0.0050

B;B

Vest4

0.30

MVP

0.067

MPC

0.060

ClinPred

0.016

GERP RS

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.089

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over