Genetic Variant NM_002430.3:c.3883C>T (chr22-27750995-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_002430.3(MN1):c.3883C>T(p.Arg1295*) 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1O:1

Conservation

PhyloP100: 6.81

Variant links:

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]

MN1 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MN1	NM_002430.3 link	c.3883C>T	p.Arg1295*	stop_gained	Exon 2 of 2	ENST00000302326.5	NP_002421.3	Q10571A0A024R1C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MN1	ENST00000302326.5 link	c.3883C>T	p.Arg1295*	stop_gained	Exon 2 of 2	1	NM_002430.3	ENSP00000304956.4	Q10571
MN1	ENST00000497225.1 link	n.239C>T		non_coding_transcript_exon_variant	Exon 2 of 2	1
MN1	ENST00000424656.1 link	n.235C>T		non_coding_transcript_exon_variant	Exon 2 of 3	5		ENSP00000397805.1	H7C105
MN1	ENST00000703102.1 link	n.408C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460696

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726562

show subpopulations

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CEBALID syndrome

Pathogenic:4Other:1

Feb 14, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Feb 01, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Recurrent pathogenic variant in 9 out of 25 persons -

Jul 29, 2020

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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:2Uncertain:1

Oct 31, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 26 amino acids are lost, and other gain-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26795593, 31834374, 28135719, 31839203, 31785789, 33057194, 35982159, 35591945) -

Inborn genetic diseases

Pathogenic:1

Sep 02, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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