14-65076544-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_002382.5(MAX):c.415G>A(p.Asp139Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D139E) has been classified as Uncertain significance.
Frequency
Consequence
NM_002382.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251488Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135918
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461866Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15AN XY: 727234
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74288
ClinVar
Submissions by phenotype
Pheochromocytoma Uncertain:1
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not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34923986) -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.D139N variant (also known as c.415G>A), located in coding exon 5 of the MAX gene, results from a G to A substitution at nucleotide position 415. The aspartic acid at codon 139 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary pheochromocytoma-paraganglioma Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 139 of the MAX protein (p.Asp139Asn). This variant is present in population databases (rs772397458, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MAX-related conditions. ClinVar contains an entry for this variant (Variation ID: 404103). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MAX function with a negative predictive value of 95%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at