rs149383809
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001370259.2(MEN1):c.1098A>T(p.Glu366Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001370259.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1098A>T | p.Glu366Asp | missense_variant | Exon 8 of 10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251476Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135914
GnomAD4 exome AF: 0.000145 AC: 212AN: 1461880Hom.: 1 Cov.: 32 AF XY: 0.000142 AC XY: 103AN XY: 727244
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74488
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Uncertain:2Benign:2
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This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not specified Uncertain:1
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not provided Uncertain:1
In the published literature, this variant has been reported in families with multiple endocrine neoplasia (PMID: 16563611 (2006)). However, a functional studies observed that this variant resulted in protein levels comparable or slightly lower than the wild type (PMID: 21819486 (2011) and 35941657 (2022)). It was found in breast cancer cases as well as control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MEN1)).This variant was also identified in apparently healthy individuals (PMID: 22995991 (2013)). The frequency of this variant in the general population, 0.00014 (16/113764 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at