rs149435615
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_002334.4(LRP4):c.1769G>A(p.Arg590His) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00021 ( 0 hom. )
Consequence
LRP4
NM_002334.4 missense
NM_002334.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 4.11
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, LRP4
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP4 | NM_002334.4 | c.1769G>A | p.Arg590His | missense_variant | 14/38 | ENST00000378623.6 | |
LRP4 | XM_017017734.2 | c.1769G>A | p.Arg590His | missense_variant | 14/39 | ||
LRP4 | XM_011520103.3 | c.965G>A | p.Arg322His | missense_variant | 8/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP4 | ENST00000378623.6 | c.1769G>A | p.Arg590His | missense_variant | 14/38 | 1 | NM_002334.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000224 AC: 34AN: 152118Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000103 AC: 26AN: 251214Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135812
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GnomAD4 exome AF: 0.000207 AC: 303AN: 1461824Hom.: 0 Cov.: 33 AF XY: 0.000199 AC XY: 145AN XY: 727224
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GnomAD4 genome ? AF: 0.000224 AC: 34AN: 152118Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15AN XY: 74294
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
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 | Fulgent Genetics, Fulgent Genetics | Mar 19, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 590 of the LRP4 protein (p.Arg590His). This variant is present in population databases (rs149435615, gnomAD 0.02%). 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: 304882). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Cenani-Lenz syndactyly syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at