rs139006210

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BS1_Supporting

The NM_002334.4(LRP4):c.1130A>G(p.Gln377Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 0 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.47

Variant links:

Genes affected

LRP4 (HGNC:6696): (LDL receptor related protein 4) This gene encodes a member of the low-density lipoprotein receptor-related protein family. The encoded protein may be a regulator of Wnt signaling. Mutations in this gene are associated with Cenani-Lenz syndrome. [provided by RefSeq, May 2010]

LRP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, LRP4

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000605 (885/1461618) while in subpopulation NFE AF= 0.00077 (856/1111966). AF 95% confidence interval is 0.000726. There are 0 homozygotes in gnomad4_exome. There are 415 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP4	NM_002334.4 linkuse as main transcript	c.1130A>G	p.Gln377Arg	missense_variant	10/38	ENST00000378623.6
LRP4	XM_017017734.2 linkuse as main transcript	c.1130A>G	p.Gln377Arg	missense_variant	10/39
LRP4	XM_011520103.3 linkuse as main transcript	c.326A>G	p.Gln109Arg	missense_variant	4/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6 linkuse as main transcript	c.1130A>G	p.Gln377Arg	missense_variant	10/38	1	NM_002334.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000382

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000211

AC:

AN:

251144

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000605

AC:

885

AN:

1461618

Hom.:

Cov.:

AF XY:

0.000571

AC XY:

415

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000752

Gnomad4 NFE exome

AF:

0.000770

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000204

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000402

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 377 of the LRP4 protein (p.Gln377Arg). This variant is present in population databases (rs139006210, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with LRP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 535798). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 18, 2022	- -

Cenani-Lenz syndactyly syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

The c.1130A>G (p.Q377R) alteration is located in exon 10 (coding exon 10) of the LRP4 gene. This alteration results from a A to G substitution at nucleotide position 1130, causing the glutamine (Q) at amino acid position 377 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.24

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.19

Eigen

Benign

-0.082

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.14

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.54

Sift

Benign

0.39

Sift4G

Benign

0.38

Polyphen

0.11

Vest4

0.85

MVP

0.67

MPC

0.61

ClinPred

0.070

GERP RS

5.8

Varity_R

0.35

gMVP

0.57

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

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