Variant chr11-64804694-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001370259.2(MEN1):c.1473G>C(p.Glu491Asp) 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: 33)

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.103

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]

MEN1 links:

MEN1 (HGNC:):

MEN1 links:

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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 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.3178417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1473G>C	p.Glu491Asp	missense_variant	10/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7 linkuse as main transcript	c.1473G>C	p.Glu491Asp	missense_variant	10/10	5	NM_001370259.2	ENSP00000394933.3		O00255-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2022

The p.E491D variant (also known as c.1473G>C), located in coding exon 9 of the MEN1 gene, results from a G to C substitution at nucleotide position 1473. The glutamic acid at codon 491 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.;.;.;D;D;D;D

Eigen

Benign

-0.13

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T;.;.;T;.;.;T;.

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.32

T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.3

MutationAssessor

Benign

1.2

.;.;.;.;.;L;L;L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.25

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.15

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T;T;T;T;T

Polyphen

0.0030, 0.0040

.;B;B;B;B;B;B;B;B

Vest4

0.14

MutPred

0.58

.;.;.;.;.;Loss of glycosylation at P494 (P = 0.0905);Loss of glycosylation at P494 (P = 0.0905);Loss of glycosylation at P494 (P = 0.0905);Loss of glycosylation at P494 (P = 0.0905);

MVP

0.70

MPC

2.1

ClinPred

0.85

GERP RS

4.5

Varity_R

0.21

gMVP

0.50

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over