rs1060499977

Positions:

• chr11-64810018-T-A
• chr11-64810018-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001370259.2(MEN1):​c.92A>T​(p.Glu31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,512 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E31K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.30

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001370259.2
• 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, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.92A>T	p.Glu31Val	missense_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.92A>T	p.Glu31Val	missense_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455512 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 723318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2023	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. This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 31 of the MEN1 protein (p.Glu31Val). 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. ClinVar contains an entry for this variant (Variation ID: 403813). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 30, 2024

The p.E31V variant (also known as c.92A>T), located in coding exon 1 of the MEN1 gene, results from an A to T substitution at nucleotide position 92. The glutamic acid at codon 31 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	.;M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen		0.97, 1.0	.;D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.50
MutPred		0.82		Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);
MVP		0.94
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1060499977; hg19: chr11-64577490;