chr6-26091475-G-C
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong
The NM_000410.4(HFE):c.502G>C(p.Glu168Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E168E) has been classified as Likely benign.
Frequency
Consequence
NM_000410.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000460 AC: 70AN: 152202Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.000446 AC: 112AN: 251276 AF XY: 0.000508 show subpopulations
GnomAD4 exome AF: 0.000666 AC: 974AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.000630 AC XY: 458AN XY: 727236 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000460 AC: 70AN: 152322Hom.: 0 Cov.: 31 AF XY: 0.000550 AC XY: 41AN XY: 74486 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hemochromatosis type 1 Uncertain:4
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not provided Uncertain:3
BP4 -
Identified in individuals with hereditary hemochromatosis; however, all reported individuals also harbored other variants in the HFE gene and it remains unclear whether this variant is sufficient to cause disease (PMID: 10953950, 12537660, 12681966, 15477198, 19214108, 19787796); Identified in a patient with hyperferritinemia and analyses suggested this variant was in cis with the p.(His63Asp) variant (PMID: 29084376); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12870733, 12681966, 15477198, 12537660, 12952143, 15025725, 19214108, 19787796, 29590070, 34426522, 10953950, 19759876, 29084376) -
HFE: PM2, BP4 -
not specified Uncertain:1
Classification criteria: BP4 -
Hereditary hemochromatosis Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 168 of the HFE protein (p.Glu168Gln). This variant is present in population databases (rs146519482, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hemochromatosis (PMID: 10953950, 12681966, 15025725, 15477198, 19214108, 19787796). ClinVar contains an entry for this variant (Variation ID: 222651). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HFE protein function with a negative predictive value of 80%. 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. -
Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C1863052:Alzheimer disease type 1;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2;C3469186:Hemochromatosis type 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at