rs765240067
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting
The NM_002334.4(LRP4):c.4144C>T(p.Pro1382Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000028 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
LRP4
NM_002334.4 missense
NM_002334.4 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 6.40
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, LRP4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.20092916).
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000028 (41/1461874) while in subpopulation SAS AF= 0.000406 (35/86258). AF 95% confidence interval is 0.0003. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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 | UniProt |
---|---|---|---|---|---|---|---|
LRP4 | NM_002334.4 | c.4144C>T | p.Pro1382Ser | missense_variant | 28/38 | ENST00000378623.6 | |
LRP4 | XM_017017734.2 | c.4144C>T | p.Pro1382Ser | missense_variant | 28/39 | ||
LRP4 | XM_011520103.3 | c.3340C>T | p.Pro1114Ser | missense_variant | 22/32 | ||
LRP4 | XM_011520104.3 | c.1909C>T | p.Pro637Ser | missense_variant | 13/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP4 | ENST00000378623.6 | c.4144C>T | p.Pro1382Ser | missense_variant | 28/38 | 1 | NM_002334.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251330Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135832
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GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727238
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
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ExAC
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5
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
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 | Dec 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 20, 2022 | 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. 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 C65"). ClinVar contains an entry for this variant (Variation ID: 573237). This variant has not been reported in the literature in individuals affected with LRP4-related conditions. This variant is present in population databases (rs765240067, gnomAD 0.04%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1382 of the LRP4 protein (p.Pro1382Ser). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at