11-64804527-T-A

Variant names:

• chr11-64804527-T-A
• NM_001370259.2:c.1640A>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.1640A>T​(p.Glu547Val) 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: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11

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 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=0.36604798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1640A>T	p.Glu547Val	missense_variant	Exon 10 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1640A>T	p.Glu547Val	missense_variant	Exon 10 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E547V variant (also known as c.1640A>T), located in coding exon 9 of the MEN1 gene, results from an A to T substitution at nucleotide position 1640. The glutamic acid at codon 547 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;.;.;.;.;D;D;D;D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D;T;.;.;T;.;.;T;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.69	.;.;.;.;.;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.015	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.098	T;T;T;T;T;T;T;T;T
Polyphen		0.087, 0.18, 0.21	.;B;B;B;B;B;B;B;B
Vest4		0.25
MutPred		0.47		.;.;.;.;.;Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);
MVP		0.71
MPC		1.6
ClinPred		0.73	D
GERP RS		4.3
Varity_R		0.20
gMVP		0.52

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: chr11-64571999;