11-64804776-G-C

Variant names:

• chr11-64804776-G-C
• rs778728934
• NM_001370259.2:c.1391C>G

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.1391C>G​(p.Ala464Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,594 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A464V) 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: 3.71
• Publications: 1 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 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=0.27627373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1391C>G	p.Ala464Gly	missense_variant	Exon 10 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1391C>G	p.Ala464Gly	missense_variant	Exon 10 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444594 Hom.: 0 Cov.: 43 AF XY: 0.00000139 AC XY: 1 AN XY: 718830

⚠️ 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: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110896

Other (OTH) AF: 0.00 AC: 0 AN: 60138

⚠️ 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;.;.;.;.;D;D;D;D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T;T;.;.;T;.;.;T;.
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	0.0	.;.;.;.;.;N;N;N;N
PhyloP100		3.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.27	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T
Vest4		0.21
ClinPred		0.56	D
GERP RS		4.5
Varity_R		0.064
gMVP		0.67
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778728934; hg19: chr11-64572248;