rs1555166357

chr11-64809712-T-Cchr11-64809712-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001370259.2(MEN1):c.398A>G(p.Tyr133Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y133Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MEN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.398A>G	p.Tyr133Cys	missense_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.398A>G	p.Tyr133Cys	missense_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MEN1-related disease. This sequence change replaces tyrosine with cysteine at codon 133 of the MEN1 protein (p.Tyr133Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen		1.0	.;D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.73
MutPred		0.79		Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);Loss of stability (P = 0.0155);
MVP		0.98
MPC		2.4
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.98

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: rs1555166357; hg19: chr11-64577184;