rs1555164153

Variant names:

• chr11-64805051-C-A
• rs1555164153
• NM_001370259.2:c.1333G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64805051-C-A
• chr11-64805051-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370259.2(MEN1):​c.1333G>T​(p.Gly445Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1333G>T	p.Gly445Cys	missense_variant	Exon 9 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1333G>T	p.Gly445Cys	missense_variant	Exon 9 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Sep 21, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with cysteine at codon 445 of the MEN1 protein (p.Gly445Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MEN1-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;.;.;.;D;D;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	.;.;.;.;L;L;L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.019	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D
Vest4		0.54
MutPred		0.58		.;.;.;.;Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.88
MPC		2.2
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.38
gMVP		0.92

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: rs1555164153; hg19: chr11-64572523;