rs878856863

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001370259.2(MEN1):​c.215C>T​(p.Pro72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Consequence

MEN1
NM_001370259.2 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17
Variant links:
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
BP4
Computational evidence support a benign effect (MetaRNN=0.35269725).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEN1NM_001370259.2 linkc.215C>T p.Pro72Leu missense_variant Exon 2 of 10 ENST00000450708.7 NP_001357188.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEN1ENST00000450708.7 linkc.215C>T p.Pro72Leu missense_variant Exon 2 of 10 5 NM_001370259.2 ENSP00000394933.3 O00255-2

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1
Nov 15, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the MEN1 protein (p.Pro72Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. 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 not expected to disrupt MEN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.60
D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.099
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.93
D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.35
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Benign
1.3
.;L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.79
N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.60
Sift
Benign
0.43
T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.78
T;T;T;T;T;T;T;T;T;.;T;T;.;.
Polyphen
0.041, 0.16, 0.051
.;B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4
0.34
MutPred
0.50
Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);Loss of catalytic residue at P71 (P = 0.0165);
MVP
0.81
MPC
1.1
ClinPred
0.56
D
GERP RS
4.9
Varity_R
0.45
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64577367; API