rs2959656

chr11-64804546-T-Cchr11-64804546-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T541E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.90 (62591 hom., cov: 33)
  • Exomes 𝑓: 0.98 (700974 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.139

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MEN1
• 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	UniProt
MEN1	NM_001370259.2	c.1621A>G	p.Thr541Ala	missense_variant	10/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1621A>G	p.Thr541Ala	missense_variant	10/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136517 AN: 152104 Hom.: 62559 Cov.: 33

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

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.: 69 AF XY: 0.979 AC XY: 712107 AN XY: 727040

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.: 33 AF XY: 0.897 AC XY: 66721 AN XY: 74400

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2018	- -
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 -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	Color Diagnostics, LLC DBA Color Health	Mar 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.50	T
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	N
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	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs2959656; hg19: chr11-64572018; COSMIC: COSV53639974; COSMIC: COSV53639974;