rs1555163642

chr11-64804694-C-Gchr11-64804694-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E491A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MEN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3178417).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1473G>C	p.Glu491Asp	missense_variant	10/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	18
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	D
LIST_S2	Benign	0.78	T;T;.;.;T;.;.;T;.
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.3	D
MutationTaster	Benign	0.60	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
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	D
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.

Other links and lift over

hg19: chr11-64572166;