rs786204066

Variant names:

• chr11-64804758-G-C
• rs750112288
• NM_001370259.2:c.1409C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-64804758-G-C
• chr11-64804758-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001407150.1(MEN1):​c.1550C>G​(p.Pro517Arg) 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. 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. P517L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001407150.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. 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: NaN (below 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28063247).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407150.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.1409C>G	p.Pro470Arg	missense	Exon 10 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.1550C>G	p.Pro517Arg	missense	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1535C>G	p.Pro512Arg	missense	Exon 11 of 11	NP_001357180.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.1409C>G	p.Pro470Arg	missense	Exon 10 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.1409C>G	p.Pro470Arg	missense	Exon 10 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.1409C>G	p.Pro470Arg	missense	Exon 11 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.0	L
PhyloP100		1.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.40
Sift	Benign	0.10	T
Sift4G	Benign	0.51	T
Polyphen		0.078	B
Vest4		0.20
MutPred		0.40		Gain of helix (P = 0.0022)
MVP		0.60
MPC		1.7
ClinPred		0.16	T
GERP RS		2.5
Varity_R		0.065
gMVP		0.65
Mutation Taster		=84/16	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: rs750112288; hg19: chr11-64572230;