rs2959656

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001370259.2(MEN1):c.1621A>G(p.Thr541Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,613,650 control chromosomes in the GnomAD database, including 763,565 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 62591 hom., cov: 33)

Exomes 𝑓: 0.98 ( 700974 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.139

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 Benign. Variant got -19 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=6.717767E-7).

BP6

Variant 11-64804546-T-C is Benign according to our data. Variant chr11-64804546-T-C is described in ClinVar as [Benign]. Clinvar id is 134640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64804546-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1621A>G	p.Thr541Ala	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.1621A>G	p.Thr541Ala	missense_variant	10/10	5	NM_001370259.2	ENSP00000394933.3		O00255-2

Frequencies

GnomAD3 genomes

AF:

0.898

AC:

136517

AN:

152104

Hom.:

62559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.713

Gnomad AMI

AF:

0.993

Gnomad AMR

AF:

0.903

Gnomad ASJ

AF:

0.997

Gnomad EAS

AF:

0.701

Gnomad SAS

AF:

0.986

Gnomad FIN

AF:

0.983

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.996

Gnomad OTH

AF:

0.924

GnomAD3 exomes

AF:

0.937

AC:

235276

AN:

250986

Hom.:

111643

AF XY:

0.949

AC XY:

128788

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.706

Gnomad AMR exome

AF:

0.881

Gnomad ASJ exome

AF:

0.996

Gnomad EAS exome

AF:

0.697

Gnomad SAS exome

AF:

0.995

Gnomad FIN exome

AF:

0.982

Gnomad NFE exome

AF:

0.996

Gnomad OTH exome

AF:

0.964

GnomAD4 exome

AF:

0.977

AC:

1428180

AN:

1461428

Hom.:

700974

Cov.:

AF XY:

0.979

AC XY:

712107

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.700

Gnomad4 AMR exome

AF:

0.884

Gnomad4 ASJ exome

AF:

0.995

Gnomad4 EAS exome

AF:

0.733

Gnomad4 SAS exome

AF:

0.994

Gnomad4 FIN exome

AF:

0.982

Gnomad4 NFE exome

AF:

0.997

Gnomad4 OTH exome

AF:

0.959

GnomAD4 genome

AF:

0.897

AC:

136597

AN:

152222

Hom.:

62591

Cov.:

AF XY:

0.897

AC XY:

66721

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.713

Gnomad4 AMR

AF:

0.903

Gnomad4 ASJ

AF:

0.997

Gnomad4 EAS

AF:

0.701

Gnomad4 SAS

AF:

0.986

Gnomad4 FIN

AF:

0.983

Gnomad4 NFE

AF:

0.996

Gnomad4 OTH

AF:

0.925

Alfa

AF:

0.969

Hom.:

60907

Bravo

AF:

0.881

TwinsUK

AF:

0.997

AC:

3696

ALSPAC

AF:

0.996

AC:

3839

ESP6500AA

AF:

0.738

AC:

3247

ESP6500EA

AF:

0.996

AC:

8559

ExAC

AF:

0.938

AC:

113841

Asia WGS

AF:

0.868

AC:

3022

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2018	- -
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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Multiple endocrine neoplasia, type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2018	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.6

DANN

Benign

0.54

DEOGEN2

Benign

0.22

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.029

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

MetaRNN

Benign

6.7e-7

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.69

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

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.69

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

REVEL

Uncertain

0.30

Sift

Benign

0.87

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

Sift4G

Benign

0.76

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

Polyphen

0.0

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

Vest4

0.053

MPC

1.0

ClinPred

0.0012

GERP RS

3.4

Varity_R

0.021

gMVP

0.27

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