5-38481601-G-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001127671.2(LIFR):c.3288C>A(p.Asn1096Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,614,062 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001127671.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LIFR | ENST00000453190.7 | c.3288C>A | p.Asn1096Lys | missense_variant | Exon 20 of 20 | 2 | NM_001127671.2 | ENSP00000398368.2 | ||
LIFR | ENST00000263409.8 | c.3288C>A | p.Asn1096Lys | missense_variant | Exon 20 of 20 | 1 | ENSP00000263409.4 |
Frequencies
GnomAD3 genomes AF: 0.00176 AC: 268AN: 152138Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00150 AC: 376AN: 250856Hom.: 0 AF XY: 0.00173 AC XY: 235AN XY: 135836
GnomAD4 exome AF: 0.00190 AC: 2771AN: 1461806Hom.: 3 Cov.: 32 AF XY: 0.00187 AC XY: 1361AN XY: 727200
GnomAD4 genome AF: 0.00176 AC: 268AN: 152256Hom.: 1 Cov.: 32 AF XY: 0.00188 AC XY: 140AN XY: 74442
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
LIFR: BS1 -
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28334964) -
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Stuve-Wiedemann syndrome Benign:2
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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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not specified Uncertain:1
Variant summary: LIFR c.3288C>A (p.Asn1096Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250856 control chromosomes. The observed variant frequency is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in LIFR causing Stuve-Wiedemann Syndrome phenotype (0.0011), suggesting that the variant may be benign. c.3288C>A has been reported in the literature in individuals affected with congenital anomalies of the kidneys and urinary tract (Kosfeld_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Stuve-Wiedemann Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Kosfeld_2017). ClinVar contains an entry for this variant (Variation ID: 353605). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Stüve-Wiedemann syndrome 1 Uncertain:1
The LIFR c.3288C>A; p.Asn1096Lys variant (rs3729751) is reported in the literature in several individuals affected with urinary tract malformations as well as in a healthy parent (Kosfeld 2017), but it has not, to our knowledge, been reported in association with skeletal dysplasia. This variant is reported with discrepant classifications in the ClinVar database (Variation ID: 353605) and is found in the non-Finnish European population with an allele frequency of 0.28% (363/129,018 alleles) in the Genome Aggregation Database. The asparagine at codon 1096 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Functional studies suggest the variant protein is expressed in the cell at wildtype levels but may exhibit slightly diminished cell-surface expression, although it is unclear if this difference is clinically significant (Kosfeld 2017). Due to limited information, the clinical significance of the p.Asn1096Lys variant is uncertain at this time. References: Kosfeld et al. Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations. Hum Mol Genet. 2017 May 1;26(9):1716-1731. PMID: 28334964. -
Congenital anomaly of kidney and urinary tract Uncertain:1
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LIFR-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at