11-64804689-G-T

Variant names:

• chr11-64804689-G-T
• rs766604600
• NM_001370259.2:c.1478C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370259.2(MEN1):​c.1478C>A​(p.Pro493Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P493L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• 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 3 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.

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.1478C>A	p.Pro493Gln	missense	Exon 10 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.1619C>A	p.Pro540Gln	missense	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1604C>A	p.Pro535Gln	missense	Exon 11 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.1478C>A	p.Pro493Gln	missense	Exon 10 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.1478C>A	p.Pro493Gln	missense	Exon 10 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.1478C>A	p.Pro493Gln	missense	Exon 11 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442292 Hom.: 0 Cov.: 43 AF XY: 0.00000139 AC XY: 1 AN XY: 717328

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33072

American (AMR) AF: 0.00 AC: 0 AN: 43336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 85726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107638

Other (OTH) AF: 0.00 AC: 0 AN: 59712

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L
PhyloP100		4.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.42
Sift	Benign	0.10	T
Sift4G	Benign	0.55	T
Polyphen		0.96	D
Vest4		0.30
MutPred		0.47		Loss of glycosylation at P498 (P = 0.0015)
MVP		0.75
MPC		2.1
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.10
gMVP		0.62
Mutation Taster		=75/25	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: rs766604600; hg19: chr11-64572161;