rs780336679
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_002334.4(LRP4):c.316+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,611,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_002334.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP4 | NM_002334.4 | c.316+1G>A | splice_donor_variant | ENST00000378623.6 | |||
LRP4 | XM_017017734.2 | c.316+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP4 | ENST00000378623.6 | c.316+1G>A | splice_donor_variant | 1 | NM_002334.4 | P1 | |||
LRP4 | ENST00000534404.1 | c.169+1G>A | splice_donor_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251454Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1459630Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 726318
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74368
ClinVar
Submissions by phenotype
Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2023 | This sequence change affects a donor splice site in intron 3 of the LRP4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LRP4 are known to be pathogenic (PMID: 23636941, 24924585). This variant is present in population databases (rs780336679, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with Cenani-Lenz syndactyly syndrome (PMID: 28559208). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428601). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 17, 2021 | - - |
Cenani-Lenz syndactyly syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Charité Universitaetsmedizin Berlin | Mar 21, 2017 | This variant was observed in a homozygous state in the index and the two affected siblings while all other probands carried the variant in a heterozygous state. The retained intron 3 would add 29 non-native amino acids in the protein with a premature stop codon leading to a truncated protein. The detected novel variant is bioinformatically predicted to be disease-causing (online tools MutationTester, NetGene2, NNSPLICE), and is found in the general population with a very low heterozygote frequency of approximately 1/20,000 (ExAC database). Therefore, the variant is considered to be causative for the observed phenotype. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at