NM_001370259.2:c.352G>T

Variant names:

• chr11-64809758-C-A
• rs1060499975
• NM_001370259.2:c.352G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001370259.2(MEN1):​c.352G>T​(p.Val118Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V118M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.38
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.352G>T	p.Val118Leu	missense_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.352G>T	p.Val118Leu	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	.;M;M;M;M;M;M;M;M;.;.;.;.;.
PhyloP100		5.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.011	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen		0.74, 0.91, 0.93	.;P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.76
MutPred		0.73		Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);Loss of methylation at K119 (P = 0.0342);
MVP		0.97
MPC		1.6
ClinPred		0.97	D
GERP RS		4.9
PromoterAI		0.0052	Neutral
Varity_R		0.75
gMVP		0.93
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs1060499975; hg19: chr11-64577230;