rs763160290

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM5PP2BS2

The NM_001370259.2(MEN1):c.1546C>T(p.Arg516Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,606,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R516G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.09

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 Likely_benign. Variant got -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-64804621-G-C 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.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2 linkuse as main transcript	c.1546C>T	p.Arg516Trp	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.1546C>T	p.Arg516Trp	missense_variant	10/10	5	NM_001370259.2	ENSP00000394933	P3	O00255-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

236576

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

129290

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000189

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1454248

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

723334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2021	The p.R516W variant (also known as c.1546C>T), located in coding exon 9 of the MEN1 gene, results from a C to T substitution at nucleotide position 1546. The arginine at codon 516 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Multiple endocrine neoplasia, type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 516 of the MEN1 protein (p.Arg516Trp). This variant is present in population databases (rs763160290, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of MEN1-related conditions (PMID: 31159747). This variant is also known as c.1561C>T (p.Arg521Trp). ClinVar contains an entry for this variant (Variation ID: 584527). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MEN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

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

Eigen

Benign

-0.083

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

0.93

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

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

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0030

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;D;D;D;D;D

Polyphen

0.99, 0.99

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

Vest4

0.29

MutPred

0.59

.;.;.;.;.;Gain of ubiquitination at K522 (P = 0.0249);Gain of ubiquitination at K522 (P = 0.0249);Gain of ubiquitination at K522 (P = 0.0249);Gain of ubiquitination at K522 (P = 0.0249);

MVP

0.73

MPC

2.1

ClinPred

0.62

GERP RS

2.4

Varity_R

0.20

gMVP

0.67

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