rs1060499993

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_001370259.2(MEN1):c.1481C>T(p.Pro494Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000069 in 1,594,226 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.81

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]

MEN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.31724232).

BP6

Variant 11-64804686-G-A is Benign according to our data. Variant chr11-64804686-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2 link	c.1481C>T	p.Pro494Leu	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 link	c.1481C>T	p.Pro494Leu	missense_variant	Exon 10 of 10	5	NM_001370259.2	ENSP00000394933.3		O00255-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000693

AC:

AN:

1442046

Hom.:

Cov.:

AF XY:

0.00000837

AC XY:

AN XY:

717174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000452

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Uncertain:1Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 24, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Feb 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P494L variant (also known as c.1481C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1481. The proline at codon 494 is replaced by leucine, an amino acid with similar properties. This alteration was identified in an individual with ACTH-independent macronodular adrenal hyperplasia and a thyroid adenoma (Hsiao HP et al. J Clin Endocrinol Metab, 2009 Aug;94:2930-7). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.;.;.;.;D;D;D;D

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.80

T;T;.;.;T;.;.;T;.

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.32

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.1

.;.;.;.;.;L;L;L;L

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.72

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.14

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T;T;T;T;T

Polyphen

0.0010, 0.0020

.;B;B;B;B;B;B;B;B

Vest4

0.28

MutPred

0.49

.;.;.;.;.;Loss of glycosylation at P499 (P = 8e-04);Loss of glycosylation at P499 (P = 8e-04);Loss of glycosylation at P499 (P = 8e-04);Loss of glycosylation at P499 (P = 8e-04);

MVP

0.62

MPC

1.1

ClinPred

0.20

GERP RS

3.6

Varity_R

0.044

gMVP

0.50

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over