11-64809956-G-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_001370259.2(MEN1):āc.154C>Gā(p.Arg52Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ).
Frequency
Genomes: not found (cov: 30)
Exomes š: 7.0e-7 ( 0 hom. )
Consequence
MEN1
NM_001370259.2 missense
NM_001370259.2 missense
Scores
8
10
1
Clinical Significance
Conservation
PhyloP100: 2.68
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.92
PP5
Variant 11-64809956-G-C is Pathogenic according to our data. Variant chr11-64809956-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1037243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64809956-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.154C>G | p.Arg52Gly | missense_variant | 2/10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEN1 | ENST00000450708.7 | c.154C>G | p.Arg52Gly | missense_variant | 2/10 | 5 | NM_001370259.2 | ENSP00000394933.3 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome AF: 6.97e-7 AC: 1AN: 1433810Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 711010
GnomAD4 exome
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1
AN:
1433810
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35
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0
AN XY:
711010
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 28, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 1037243). This missense change has been observed in individuals with clinical features of MEN1-related conditions (PMID: 21454242; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 52 of the MEN1 protein (p.Arg52Gly). Experimental studies have shown that this missense change affects MEN1 function (PMID: 35941657). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen
1.0, 0.90, 0.92
.;D;P;P;P;P;P;P;P;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);Gain of catalytic residue at V53 (P = 0.016);
MVP
MPC
2.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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