rs2071313

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001370259.2(MEN1):c.1254C>T(p.Asp418=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,613,902 control chromosomes in the GnomAD database, including 132,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 9444 hom., cov: 33)

Exomes 𝑓: 0.40 ( 122584 hom. )

Consequence

MEN1
NM_001370259.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.00600

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-64805130-G-A is Benign according to our data. Variant chr11-64805130-G-A is described in ClinVar as [Benign]. Clinvar id is 96249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805130-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.006 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1254C>T	p.Asp418=	synonymous_variant	9/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7 linkuse as main transcript	c.1254C>T	p.Asp418=	synonymous_variant	9/10	5	NM_001370259.2	P3	O00255-2

Frequencies

GnomAD3 genomes

AF:

0.318

AC:

48417

AN:

152064

Hom.:

9443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0893

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.325

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.452

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.346

GnomAD3 exomes

AF:

0.392

AC:

98289

AN:

250996

Hom.:

20511

AF XY:

0.404

AC XY:

54815

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.0819

Gnomad AMR exome

AF:

0.340

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.384

Gnomad SAS exome

AF:

0.491

Gnomad FIN exome

AF:

0.439

Gnomad NFE exome

AF:

0.421

Gnomad OTH exome

AF:

0.396

GnomAD4 exome

AF:

0.405

AC:

591624

AN:

1461718

Hom.:

122584

Cov.:

AF XY:

0.409

AC XY:

297212

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.0756

Gnomad4 AMR exome

AF:

0.334

Gnomad4 ASJ exome

AF:

0.341

Gnomad4 EAS exome

AF:

0.381

Gnomad4 SAS exome

AF:

0.481

Gnomad4 FIN exome

AF:

0.436

Gnomad4 NFE exome

AF:

0.413

Gnomad4 OTH exome

AF:

0.390

GnomAD4 genome

AF:

0.318

AC:

48421

AN:

152184

Hom.:

9444

Cov.:

AF XY:

0.322

AC XY:

23940

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0893

Gnomad4 AMR

AF:

0.325

Gnomad4 ASJ

AF:

0.352

Gnomad4 EAS

AF:

0.379

Gnomad4 SAS

AF:

0.491

Gnomad4 FIN

AF:

0.452

Gnomad4 NFE

AF:

0.416

Gnomad4 OTH

AF:

0.347

Alfa

AF:

0.375

Hom.:

7056

Bravo

AF:

0.294

Asia WGS

AF:

0.434

AC:

1508

AN:

3478

EpiCase

AF:

0.414

EpiControl

AF:

0.411

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 15, 2016	p.Asp423Asp in exon 10 of MEN1: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence. It ha s been identified in 42% (53295/126568) of European chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs2071313). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Eurofins Ntd Llc (ga)	Jun 22, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Multiple endocrine neoplasia, type 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2014

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. -

Hyperparathyroidism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

Cadd

Benign

6.1

Dann

Benign

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

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