rs376872829

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM5PP2PP3BP6BS2

The NM_001370259.2(MEN1):​c.526G>T​(p.Ala176Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A176P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

9
7
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.01
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-64808019-C-G is described in Lovd as [Pathogenic].
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, pituitary gigantism, familial isolated hyperparathyroidism.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.836
BP6
Variant 11-64808019-C-A is Benign according to our data. Variant chr11-64808019-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 485714.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEN1NM_001370259.2 linkc.526G>T p.Ala176Ser missense_variant Exon 3 of 10 ENST00000450708.7 NP_001357188.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEN1ENST00000450708.7 linkc.526G>T p.Ala176Ser missense_variant Exon 3 of 10 5 NM_001370259.2 ENSP00000394933.3 O00255-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251222
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135822
show subpopulations
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:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461860
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727234
show subpopulations
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:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 11, 2024This missense variant replaces alanine with serine at codon 176 of the MEN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 3 individuals or families affected with MEN1 (PMID: 30820182). A different missense variant at this codon, p.Ala176Pro, is considered disease-causing in ClinVar (variation ID 200975) and has been detected in a family affected with MEN1 (PMID: 9215689) and functional studies have shown the p.Ala176Pro variant to be unstable and exhibited loss of function in the binding and regulation of JunD and in homology-directed repair and response to DNA damage (PMID: 9989505, 11221882, 12509449, 22090276, 23648481). This variant has been identified in 5/251222 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2025- -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 14, 2024- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 01, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitterclinical testingGeneKor MSAAug 01, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 12, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals undergoing testing for Multiple Endocrine Neoplasia Type 1, with no phenotypic details provided (Isailovic 2019); This variant is associated with the following publications: (PMID: 31159747, 9989505, 30820182) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;.;.;D;D;D;D;D;.;D
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D;D;.;.;D;.;.;D;.;D;D;D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.2
.;.;.;.;.;M;M;M;M;.;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-2.5
N;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.87
Sift
Benign
0.042
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.061
T;T;T;T;T;T;T;T;T;.;T;T
Polyphen
1.0, 0.92, 0.97
.;D;P;P;P;D;D;D;D;.;.;.
Vest4
0.58
MVP
0.88
MPC
2.1
ClinPred
0.79
D
GERP RS
4.8
Varity_R
0.72
gMVP
0.91

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376872829; hg19: chr11-64575491; API