11-64804661-C-G

Position:

chr11-64804661-C-G

Variant summary

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

The NM_001370259.2(MEN1):c.1506G>C(p.Lys502Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,599,226 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 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.508

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:

MEN1 (HGNC:):

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 gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.

BP4

Computational evidence support a benign effect (MetaRNN=0.26863402).

BP6

Variant 11-64804661-C-G is Benign according to our data. Variant chr11-64804661-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403821.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=2}.

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1506G>C	p.Lys502Asn	missense_variant	10/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7 linkuse as main transcript	c.1506G>C	p.Lys502Asn	missense_variant	10/10	5	NM_001370259.2	ENSP00000394933.3		O00255-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000136

AC:

AN:

221350

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122352

show subpopulations

Gnomad AFR exome

AF:

0.000230

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000415

AC:

AN:

1447024

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719648

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

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:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.000112

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000410

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2022	This alteration is classified as 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 submitter	curation	Sema4, Sema4	Jan 01, 2022	- -

Multiple endocrine neoplasia, type 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 06, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

MEN1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2022

The MEN1 c.1521G>C variant is predicted to result in the amino acid substitution p.Lys507Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64572133-C-G) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/403821/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.0025

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

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

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.27

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

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

0.90

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

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.0

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

REVEL

Uncertain

0.31

Sift

Benign

0.031

D;T;T;T;T;D;D;D;D

Sift4G

Benign

0.21

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

Polyphen

0.30, 0.35

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

Vest4

0.25

MutPred

0.36

.;.;.;.;.;Loss of methylation at K507 (P = 0.0021);Loss of methylation at K507 (P = 0.0021);Loss of methylation at K507 (P = 0.0021);Loss of methylation at K507 (P = 0.0021);

MVP

0.76

MPC

1.7

ClinPred

0.10

GERP RS

2.6

Varity_R

0.095

gMVP

0.82

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