11-64809917-G-T

Position:

• chr11-64809917-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370259.2(MEN1):​c.193C>A​(p.Pro65Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.193C>A	p.Pro65Thr	missense_variant	2/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.193C>A	p.Pro65Thr	missense_variant	2/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MEN1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 65 of the MEN1 protein (p.Pro65Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Benign	-0.079
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.9	.;L;L;L;L;L;L;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T;T;.;T;T;.;.
Polyphen		0.11, 0.0090, 0.69	.;B;B;B;B;P;P;P;P;.;.;.;.;.
Vest4		0.26
MutPred		0.50		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.79
MPC		1.2
ClinPred		0.68	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.62

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

Other links and lift over

dbSNP: rs1235900915; hg19: chr11-64577389;