rs1555164184

Variant names:

• chr11-64805072-TG-T
• rs1555164184
• NM_001370259.2:c.1311delC

Your query was ambiguous. Multiple possible variants found:

• chr11-64805072-TG-T
• chr11-64805072-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001370259.2(MEN1):​c.1311delC​(p.Thr438ProfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A437A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.35

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 145 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64805072-TG-T is Pathogenic according to our data. Variant chr11-64805072-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 650907.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1311delC	p.Thr438ProfsTer7	frameshift_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.1311delC	p.Thr438ProfsTer7	frameshift_variant	Exon 9 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Aug 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the MEN1 gene (p.Thr438Profs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 173 amino acids of the MEN1 protein. For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Arg516Glyfs*43) that lies downstream of this variant has been determined to be pathogenic (PMID: 9215689, 12112656, 17879353, 23321498). This suggests that deletion of this region of the MEN1 protein is causative of disease. This variant has not been reported in the literature in individuals with MEN1-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555164184; hg19: chr11-64572544;