rs1114167533
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001370259.2(MEN1):c.1269G>A(p.Trp423Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Consequence
MEN1
NM_001370259.2 stop_gained
NM_001370259.2 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.83
Genes affected
MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 167 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-64805115-C-T is Pathogenic according to our data. Variant chr11-64805115-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805115-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1269G>A | p.Trp423Ter | stop_gained | 9/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.1269G>A | p.Trp423Ter | stop_gained | 9/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Cov.: 56
GnomAD4 exome
Cov.:
56
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 16, 2017 | The MEN1 c.1269G>A; p.Trp423Ter variant (rs1114167533) has been described in the literature in an individual with multiple endocrine neoplasia type 1 (MEN 1) (Takagi 2006). It is reported in ClinVar (Variation ID: 428077), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Trp423Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/428077/ Takagi J et al. Multiple endocrine neoplasia type I and Cushing's syndrome due to an aggressive ACTH producing thymic carcinoid. Intern Med. 2006;45(2):81-6. Epub 2006 Feb 15. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2016 | The p.W423* pathogenic mutation (also known as c.1269G>A), located in coding exon 8 of the MEN1 gene, results from a G to A substitution at nucleotide position 1269. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This mutation has previously been reported in a Japanese male diagnosed with MEN1 (Takagi J et al. Intern. Med. 2006 Feb; 45(2):81-6). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at