rs147334255

Positions:

• chr22-27750995-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_002430.3(MN1):​c.3883C>T​(p.Arg1295Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MN1 NM_002430.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:2 O:1
• Conservation: PhyloP100: 6.81

Genes affected

MN1 (HGNC:7180): (MN1 proto-oncogene, transcriptional regulator) Meningioma 1 (MN1) contains two sets of CAG repeats. It is disrupted by a balanced translocation (4;22) in a meningioma, and its inactivation may contribute to meningioma 32 pathogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-27750995-G-A is Pathogenic according to our data. Variant chr22-27750995-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 72912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-27750995-G-A is described in Lovd as [Likely_pathogenic]. Variant chr22-27750995-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MN1	NM_002430.3	c.3883C>T	p.Arg1295Ter	stop_gained	2/2	ENST00000302326.5	NP_002421.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MN1	ENST00000302326.5	c.3883C>T	p.Arg1295Ter	stop_gained	2/2	1	NM_002430.3	ENSP00000304956	P1
MN1	ENST00000497225.1	n.239C>T		non_coding_transcript_exon_variant	2/2	1
MN1	ENST00000703102.1	n.408C>T		non_coding_transcript_exon_variant	2/2
MN1	ENST00000424656.1	c.238C>T	p.Arg80Ter	stop_gained, NMD_transcript_variant	2/3	5		ENSP00000397805

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460696 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CEBALID syndrome Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 2 of 2). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. The C-terminus is responsible for protein degradation (PMID: 31839203). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Three truncating variants have been reported downstream from this variant (PMID: 31834374). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported to be de novo in nine patients with CEBALID syndrome (PMID: 31834374, 31839203). (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	Recurrent pathogenic variant in 9 out of 25 persons -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jul 29, 2020	This variant is interpreted as Pathogenic for CEBALID syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants (PM4); De novo (paternity and maternity confirmed) (PS2 upgraded to very strong); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to moderate). -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2022

The c.3883C>T (p.R1295*) alteration, located in exon 2 of the MN1 gene, results from a C to T substitution at nucleotide position 3883. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1295. This alteration occurs at the 3' terminus of the MN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and this alteration and similar truncating alterations have been reported in the literature as disease-causing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with MN1 C-terminal deletion syndrome (Mak, 2020; Miyake, 2020, DECIPHER v.9.32, Ambry internal data). Functional analysis demonstrated protein that contain the p.R1295* alteration is still expressed but with a predicted absence of the C-terminal region. Protein without the C-terminal region showed increased stability and aggregation, as well as an inhibitory effect on cell proliferation compared to wild type. Additionally, transcriptome analysis of lymphoblastoid cell lines from a heterozygous patient suggested abnormal transcriptional regulation of multiple genes (Miyake, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

MN1 C-terminal truncation (MCTT) syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

GeneDx

Dec 02, 2016

The R1295X variant in the MN1 gene has been reported previously as a de novo finding identified via whole exome sequencing in a single patient with generalized epilepsy (Helbig et al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation. The R1295X variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R1295X as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	D
Vest4		0.82
GERP RS		3.4

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: rs147334255; hg19: chr22-28146983; COSMIC: COSV56559880;