rs587777171
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_002296.4(LBR):c.1639A>G(p.Asn547Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N547S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002296.4 missense
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 |
---|---|---|---|---|---|---|---|
LBR | NM_002296.4 | c.1639A>G | p.Asn547Asp | missense_variant | 13/14 | ENST00000272163.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LBR | ENST00000272163.9 | c.1639A>G | p.Asn547Asp | missense_variant | 13/14 | 1 | NM_002296.4 | P1 | |
LBR | ENST00000338179.6 | c.1639A>G | p.Asn547Asp | missense_variant | 13/14 | 5 | P1 | ||
LBR | ENST00000441022.1 | n.114A>G | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
LBR | ENST00000651341.1 | c.*805A>G | 3_prime_UTR_variant, NMD_transcript_variant | 13/15 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727228
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Greenberg dysplasia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 15, 2018 | The LBR c.1639A>G (p.Asn547Asp) missense variant has been reported two studies (Konstantinidou et al. 2008; Clayton et al. 2010). Konstantinidou et al. (2008) identified the variant in a homozygous state in an affected fetus born to consanguineous parents who were both shown to be carriers; a second affected fetus, although untested, was also presumed to be homozygous. Clayton et al. (2010) also identified the p.Asn547Asp variant in a heterozygous state in the consanguineous parents of an affected fetus who was not tested but was presumed to be homozygous. The p.Asn547Asp variant was absent from at least 500 control chromosomes and is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database, but this frequency is based on one allele in a region of good sequencing coverage. The variant is thus presumed to be rare. Functional studies showed that the p.ASn547Asp variant exhibited a considerable decrease in NADPH binding compared to wildtype in HeLa and LBR knockout cells as well as a nearly complete loss of de novo cholesterol synthesis in LBR knockout cell lines (Tsai et al. 2016; Turner and Schlieker 2016). Based on the collective evidence, the p.Asn547Asp variant is classified as likely pathogenic for Greenberg dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2010 | - - |
Pelger-Huët anomaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 07, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at