11-64808033-C-T

Position:

chr11-64808033-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM5PP2BP4_StrongBP6BS1BS2

The NM_001370259.2(MEN1):c.512G>A(p.Arg171Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,078 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign 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. R171W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.013 ( 14 hom., cov: 32)

Exomes 𝑓: 0.018 ( 299 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:26O:2

Conservation

PhyloP100: 2.73

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 Benign. Variant got -10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-64808034-G-A is described in Lovd as [Pathogenic].

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=0.014003247).

BP6

Variant 11-64808033-C-T is Benign according to our data. Variant chr11-64808033-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41854.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=2, Benign=16, Uncertain_significance=1}. Variant chr11-64808033-C-T is described in Lovd as [Likely_benign]. Variant chr11-64808033-C-T is described in Lovd as [Pathogenic]. Variant chr11-64808033-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1935/152278) while in subpopulation NFE AF= 0.0213 (1447/68028). AF 95% confidence interval is 0.0204. There are 14 homozygotes in gnomad4. There are 924 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1935 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.512G>A	p.Arg171Gln	missense_variant	3/10	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.512G>A	p.Arg171Gln	missense_variant	3/10	5	NM_001370259.2	ENSP00000394933	P3	O00255-2

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1935

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00878

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.0120

AC:

3017

AN:

250912

Hom.:

AF XY:

0.0120

AC XY:

1632

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.00456

Gnomad AMR exome

AF:

0.00773

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.00724

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00616

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0181

AC:

26503

AN:

1461800

Hom.:

299

Cov.:

AF XY:

0.0174

AC XY:

12671

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.00776

Gnomad4 ASJ exome

AF:

0.00471

Gnomad4 EAS exome

AF:

0.00421

Gnomad4 SAS exome

AF:

0.00160

Gnomad4 FIN exome

AF:

0.00605

Gnomad4 NFE exome

AF:

0.0219

Gnomad4 OTH exome

AF:

0.0142

GnomAD4 genome

AF:

0.0127

AC:

1935

AN:

152278

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

924

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00436

Gnomad4 AMR

AF:

0.00877

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00502

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00612

Gnomad4 NFE

AF:

0.0213

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0178

Hom.:

Bravo

AF:

0.0121

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0209

AC:

180

ExAC

AF:

0.0118

AC:

1427

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0182

EpiControl

AF:

0.0198

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:26Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Uncertain:1Benign:7Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely benign and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -
Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 17, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified

Benign:7Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 01, 2020	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22995991, 20981092, 21521296, 22703879, 24997771, 21819486, 24728327, 18221402, 27153395, 30324798, 30869828) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MEN1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2015	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

Multiple endocrine neoplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

May 05, 2015

- -

Hyperparathyroidism

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;.;.;D;D;D;D;D;.;D

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.95

D;D;.;.;D;.;.;D;.;D;D;D

MetaRNN

Benign

0.014

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

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

0.69

.;.;.;.;.;N;N;N;N;.;.;.

MutationTaster

Benign

0.67

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

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.75

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

REVEL

Uncertain

0.43

Sift

Benign

0.10

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

Sift4G

Benign

0.15

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

Polyphen

0.76, 0.99, 0.99

.;P;D;D;D;D;D;D;D;.;.;.

Vest4

0.20

MPC

1.2

ClinPred

0.017

GERP RS

4.8

Varity_R

0.34

gMVP

0.78

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