11-64804686-G-T

Variant names:

• chr11-64804686-G-T
• rs1060499993
• NM_001370259.2:c.1481C>A

Variant summary

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

The NM_001370259.2(MEN1):​c.1481C>A​(p.Pro494Gln) 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. P494L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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 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 pituitary gigantism, multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, familial isolated hyperparathyroidism.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36005783).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.1481C>A	p.Pro494Gln	missense	Exon 10 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1622C>A	p.Pro541Gln	missense	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1607C>A	p.Pro536Gln	missense	Exon 11 of 11	NP_001357180.2	A0A5F9ZHS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.1481C>A	p.Pro494Gln	missense	Exon 10 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1481C>A	p.Pro494Gln	missense	Exon 10 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1481C>A	p.Pro494Gln	missense	Exon 11 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442048 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 717174

African (AFR) AF: 0.00 AC: 0 AN: 33068

American (AMR) AF: 0.00 AC: 0 AN: 43176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25864

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.00 AC: 0 AN: 85684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107348

Other (OTH) AF: 0.00 AC: 0 AN: 59700

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	0.46	N
PhyloP100		2.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.47
Sift	Benign	0.14	T
Sift4G	Benign	0.52	T
Polyphen		0.49	P
Vest4		0.30
MutPred		0.45		Loss of glycosylation at P499 (P = 8e-04)
MVP		0.64
MPC		2.0
ClinPred		0.26	T
GERP RS		3.6
Varity_R		0.049
gMVP		0.52
Mutation Taster		=74/26	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: rs1060499993; hg19: chr11-64572158;