11-64809749-C-T

Variant names:

• chr11-64809749-C-T
• rs863224812
• NM_001370259.2:c.361G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_001370259.2(MEN1):​c.361G>A​(p.Val121Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V121F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.07
• 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: Likely_benign. The variant received -2 ACMG points.

• 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, 0.824
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370259.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.361G>A	p.Val121Ile	missense	Exon 2 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.361G>A	p.Val121Ile	missense	Exon 2 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.361G>A	p.Val121Ile	missense	Exon 2 of 11	NP_001357180.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.361G>A	p.Val121Ile	missense	Exon 2 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.361G>A	p.Val121Ile	missense	Exon 2 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.361G>A	p.Val121Ile	missense	Exon 3 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251466 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000223 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Multiple endocrine neoplasia, type 1 (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	MEN1-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.65	N
REVEL	Pathogenic	0.77
Sift	Benign	0.043	D
Sift4G	Benign	0.066	T
Polyphen		0.99	D
Vest4		0.52
MutPred		0.78		Loss of methylation at K120 (P = 0.0668)
MVP		0.81
MPC		1.5
ClinPred		0.88	D
GERP RS		4.9
PromoterAI		0.030	Neutral
Varity_R		0.36
gMVP		0.86
Mutation Taster		=54/46	polymorphism

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: rs863224812; hg19: chr11-64577221;