rs886042160
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001127671.2(LIFR):c.653_654insT(p.Glu219GlyfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
LIFR
NM_001127671.2 frameshift
NM_001127671.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.75
Genes affected
LIFR (HGNC:6597): (LIF receptor subunit alpha) This gene encodes a protein that belongs to the type I cytokine receptor family. This protein combines with a high-affinity converter subunit, gp130, to form a receptor complex that mediates the action of the leukemia inhibitory factor, a polyfunctional cytokine that is involved in cellular differentiation, proliferation and survival in the adult and the embryo. Mutations in this gene cause Schwartz-Jampel syndrome type 2, a disease belonging to the group of the bent-bone dysplasias. A translocation that involves the promoter of this gene, t(5;8)(p13;q12) with the pleiomorphic adenoma gene 1, is associated with salivary gland pleiomorphic adenoma, a common type of benign epithelial tumor of the salivary gland. Multiple splice variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2018]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-38511872-C-CA is Pathogenic according to our data. Variant chr5-38511872-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 281444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIFR | NM_001127671.2 | c.653_654insT | p.Glu219GlyfsTer3 | frameshift_variant | 6/20 | ENST00000453190.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIFR | ENST00000453190.7 | c.653_654insT | p.Glu219GlyfsTer3 | frameshift_variant | 6/20 | 2 | NM_001127671.2 | P1 | |
LIFR | ENST00000263409.8 | c.653_654insT | p.Glu219GlyfsTer3 | frameshift_variant | 6/20 | 1 | P1 | ||
LIFR | ENST00000503088.1 | n.816_817insT | non_coding_transcript_exon_variant | 6/15 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727212
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LIFR are known to be pathogenic (PMID: 14740318). This variant has been observed in several individuals affected with Stuve-Wiedemann syndrome (PMID: 14740318). ClinVar contains an entry for this variant (Variation ID: 281444). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu219Glyfs*3) in the LIFR gene. It is expected to result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 19, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 08, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14740318) - |
Stuve-Wiedemann syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 16, 2022 | - - |
Stüve-Wiedemann syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1
Pathogenic, no assertion criteria provided | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Computational scores
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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