11-64805036-G-C

Variant names:

• chr11-64805036-G-C
• rs1114167509
• NM_001370259.2:c.1348C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_001370259.2(MEN1):​c.1348C>G​(p.Gln450Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Q450H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 missense, splice_region
• Scores: Splicing: ADA: 0.1073
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.39
• 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 28 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64805034-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 818932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31329143).

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.1348C>G	p.Gln450Glu	missense splice_region	Exon 9 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.1489C>G	p.Gln497Glu	missense splice_region	Exon 10 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1474C>G	p.Gln492Glu	missense splice_region	Exon 10 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.1348C>G	p.Gln450Glu	missense splice_region	Exon 9 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.1348C>G	p.Gln450Glu	missense splice_region	Exon 9 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.1348C>G	p.Gln450Glu	missense splice_region	Exon 10 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.093
Eigen_PC	Benign	0.040
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.31	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.97	L
PhyloP100		6.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.25	N
REVEL	Uncertain	0.62
Sift	Benign	0.57	T
Sift4G	Benign	0.79	T
Polyphen		0.50	P
Vest4		0.47
MutPred		0.64		Gain of ubiquitination at K459 (P = 0.0457)
MVP		0.87
MPC		1.1
ClinPred		0.77	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.93
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.11		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: rs1114167509; hg19: chr11-64572508;