rs386134247
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001370259.2(MEN1):c.1174del(p.Glu392SerfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
MEN1
NM_001370259.2 frameshift
NM_001370259.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.16
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-64805645-TC-T is Pathogenic according to our data. Variant chr11-64805645-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805645-TC-T is described in Lovd as [Pathogenic]. Variant chr11-64805645-TC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.1174del | p.Glu392SerfsTer53 | frameshift_variant | 8/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.1174del | p.Glu392SerfsTer53 | frameshift_variant | 8/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS) | May 10, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Laboratory Medicine, Soonchunhyang University Seoul Hospital | Jan 23, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2019 | This variant disrupts the C-terminus of the MEN1 protein. Other variant(s) that disrupt this region (p.Lys559Glufs*38) have been determined to be pathogenic (PMID: 10090472, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This sequence change results in a premature translational stop signal in the MEN1 gene (p.Glu392Serfs*53). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acids of the MEN1 protein. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215689). This variant is also known as 1280delG in the literature. ClinVar contains an entry for this variant (Variation ID: 265238). This variant is not present in population databases (ExAC no frequency). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2017 | The c.1174delG variant has been reported previously (as 1280delG) in association with multiple endocrine neoplasia type 1 (Agarwal et al., 1997). The c.1174delG variant causes a frameshift starting with codon Glutamic acid 392, changes this amino acid to a Serine residue and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Glu392SerfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1174delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, c.1174delG is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at