11-64810025-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001370259.2(MEN1):c.85C>G(p.Arg29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R29R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MEN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.22061351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.85C>G	p.Arg29Gly	missense_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.85C>G	p.Arg29Gly	missense_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000423 AC: 1 AN: 236556 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000943

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456374 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 723900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2020

This sequence change replaces arginine with glycine at codon 29 of the MEN1 protein (p.Arg29Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MEN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MEN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2020

The p.R29G variant (also known as c.85C>G), located in coding exon 1 of the MEN1 gene, results from a C to G substitution at nucleotide position 85. The arginine at codon 29 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.93	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	0.91	N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.53	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T;T;T;.;T;T;.;.
Polyphen		0.0, 0.0030	.;B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.33
MutPred		0.45		Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);
MVP		0.74
MPC		1.3
ClinPred		0.083	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728615; hg19: chr11-64577497;