rs764570645

Positions:

• chr11-64805022-GCTGTCCCTCAC-G
• chr11-64805022-GCTGTCCCTCAC-GCTGTCCCTCACCTGTCCCTCAC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1350+1_1350+11del variant causes a splice donor, splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.62

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: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.08947081 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64805022-GCTGTCCCTCAC-G is Pathogenic according to our data. Variant chr11-64805022-GCTGTCCCTCAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 201001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805022-GCTGTCCCTCAC-G is described in Lovd as [Pathogenic]. Variant chr11-64805022-GCTGTCCCTCAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.1350+1_1350+11del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1350+1_1350+11del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This variant causes a 11-basepair deletion in intron 9 of the MEN1 gene, abolishing the intron 9 splice donor site. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in multiple individuals affected with MEN1 and (primary hyperparathyroidism (PMID: 10090472, 16563611, 17065424, 27846313, 30324798). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MEN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 03, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 201001). Disruption of this splice site has been observed in individuals with multiple endocrine neoplasia, type 1 (PMID: 9709921, 10090472). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 9 of the MEN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This variant causes a 11-basepair deletion in intron 9 of the MEN1 gene, abolishing the intron 9 splice donor site. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in multiple individuals affected with MEN1 and primary hyperparathyroidism (PMID: 10090472, 16563611, 17065424, 27846313, 30324798). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MEN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2014

The c.1350+1_1350+11delGTGAGGGACAG splice site mutation in the MEN1 gene has been previously reported in association with multiple endocrine neoplasia type 1 (Mutch et al., 1999). Using capital letters to denote exonic sequence and lower case letters to denote intronic sequence, the normal sequence with the bases that are deleted in braces is: ACAG{del gtgagggacag}ctgc. This mutation destroys the canonical splice donor site in intron 9, and is expected to cause abnormal gene splicing. The variant is found in MEN1 panel(s). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

The c.1350+1_1350+11del11 intronic pathogenic mutation, located in intron 8 of the MEN1 gene, results from a deletion of 11 nucleotides within intron 8 of the MEN1 gene. This alteration has been seen in multiple unrelated families with clinical diagnoses and features of MEN1 (Teh BT et al. J. Clin. Endocrinol. Metab.1998 Aug;83:2621-6; Jäger AC et al. Mol. Cell. Endocrinol. 2006 Apr;249:123-32; Kong J. PLoS ONE. 2016 Nov;11(11):e0166634). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs764570645; hg19: chr11-64572494;