NM_001370259.2:c.989G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_001370259.2(MEN1):​c.989G>C​(p.Arg330Pro) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R330H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

MEN1
NM_001370259.2 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.00
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 Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_001370259.2
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEN1NM_001370259.2 linkc.989G>C p.Arg330Pro missense_variant Exon 7 of 10 ENST00000450708.7 NP_001357188.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEN1ENST00000450708.7 linkc.989G>C p.Arg330Pro missense_variant Exon 7 of 10 5 NM_001370259.2 ENSP00000394933.3 O00255-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

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
Jun 12, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, this variant has uncertain impact on MEN1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine with proline at codon 330 of the MEN1 protein (p.Arg330Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MEN1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D;.;.;.;.;D;D;D;D;D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;.;.;D;.;.;D;.;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.7
.;.;.;.;.;M;M;M;M;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.5
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.017
D;D;D;D;D;D;D;D;D;.
Polyphen
1.0, 1.0
.;D;D;D;D;D;D;D;D;.
Vest4
0.96
MutPred
0.78
.;.;.;.;.;Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);.;
MVP
0.99
MPC
2.6
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.97
gMVP
0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373135175; hg19: chr11-64573764; COSMIC: COSV53648580; COSMIC: COSV53648580; API