Genetic Variant LRP4:p.Pro1307Ala (chr11-46875462-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002334.4(LRP4):c.3919C>G(p.Pro1307Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1307S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.73

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Cenani-Lenz syndactyly syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
congenital myasthenic syndrome 17
Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sclerosteosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sclerosteosis 2
Inheritance: SD Classification: LIMITED Submitted by: Ambry Genetics

LRP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14709255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP4	NM_002334.4 link	c.3919C>G	p.Pro1307Ala	missense_variant	Exon 27 of 38	ENST00000378623.6	NP_002325.2	O75096
LRP4	XM_017017734.2 link	c.3919C>G	p.Pro1307Ala	missense_variant	Exon 27 of 39		XP_016873223.1
LRP4	XM_011520103.3 link	c.3115C>G	p.Pro1039Ala	missense_variant	Exon 21 of 32		XP_011518405.1
LRP4	XM_011520104.3 link	c.1684C>G	p.Pro562Ala	missense_variant	Exon 12 of 23		XP_011518406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6 link	c.3919C>G	p.Pro1307Ala	missense_variant	Exon 27 of 38	1	NM_002334.4	ENSP00000367888.1		O75096

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250336

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461592

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111886

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.24

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

M_CAP

Benign

0.018

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.5

PhyloP100

3.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.87

REVEL

Benign

0.29

Sift

Benign

0.30

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.16

MutPred

0.43

Loss of disorder (P = 0.0719);

MVP

0.64

MPC

0.53

ClinPred

0.074

GERP RS

2.8

Varity_R

0.060

gMVP

0.24

Mutation Taster

=63/37

polymorphism

(source)

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

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11-46875462-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over