11-64807906-G-T

Variant names:

• chr11-64807906-G-T
• rs746067825
• NM_001370259.2:c.639C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001370259.2(MEN1):​c.639C>A​(p.Ala213Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -1.42

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-64807906-G-T is Pathogenic according to our data. Variant chr11-64807906-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 748511.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.639C>A	p.Ala213Ala	synonymous_variant	Exon 3 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.639C>A	p.Ala213Ala	synonymous_variant	Exon 3 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1 Uncertain:1

May 29, 2024

Regional Center For Medical Genetics Timis, Louis Turcanu Emergency Hospital for Children Timisoara

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The variant is absent from healthy population databases (gnomAD v4.1.0). The variant was previously reported in a family with MEN1 syndrome (the patient and her mother were affected, and the father and the patient's sister were healthy and negative for this variant) (PMID: 34711244). In silico predictions and RNA studies for this variant show it is associated with strengthening of a regional cryptic splice site, 14 nucleotides loss from the final transcript, frameshift and loss of function. The missense variant NM_001370259.2:c.643G>A, located nearby and classified as P/LP, has similar in silico splicing predictions. The patient's phenotype is specific for MEN1. The variant was therefore classified as likely pathogenic, according to ACMG 2015 guidelines and ClinGen guidelines for PM2, PP1/PP4 and Splicing criteria Criteria used for classification: PM2_Supporting, PP4_Strong, PP1_Supporting, PP3, PS1_Supporting. -

Dec 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individuals with MEN1-related conditions (PMID: 34711244; Invitae). This sequence change affects codon 213 of the MEN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MEN1 protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. One publication reported that this variant is associated with altered splicing, but the presented data was not conclusive (PMID: 34711244). 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
BayesDel_noAF	Benign	-0.86
CADD	Benign	14
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: -1
DS_DL_spliceai		0.41		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746067825; hg19: chr11-64575378;