rs794728615
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001370259.2(MEN1):c.85C>T(p.Arg29Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R29R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Consequence
MEN1
NM_001370259.2 stop_gained
NM_001370259.2 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.54
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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 729 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-64810025-G-A is Pathogenic according to our data. Variant chr11-64810025-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 200970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64810025-G-A is described in Lovd as [Pathogenic]. Variant chr11-64810025-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.85C>T | p.Arg29Ter | stop_gained | 2/10 | ENST00000450708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.85C>T | p.Arg29Ter | stop_gained | 2/10 | 5 | NM_001370259.2 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Arg29*) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9832038, 10395246, 22549346, 24997771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200970). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 16, 2016 | The p.R29* pathogenic mutation (also known as c.85C>T), located in coding exon 1 of the MEN1 gene, results from a C to T substitution at nucleotide position 85. This changes the amino acid from an arginine to a premature termination codon. This mutation, also known in the literature as c.195C>T, has been reported in multiple individuals with MEN1 (Sato M et al. J Med Genet. 1998 Nov;35(11):915-9; Klein RD et al. Genet. Med. 2005 Feb; 7(2):131-8; Khoo J et al. Exp. Clin. Endocrinol. Diabetes. 2012 May; 120(5):257-60). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A
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