rs147334255

Variant names:

• chr22-27750995-G-A
• rs147334255
• NM_002430.3:c.3883C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-27750995-G-A
• chr22-27750995-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MN1 NM_002430.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1 O:1
• Conservation: PhyloP100: 6.81
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• CEBALID syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial meningioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 5 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 72912.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MN1	NM_002430.3	c.3883C>T	p.Arg1295*	stop_gained	Exon 2 of 2	ENST00000302326.5	NP_002421.3

Ensembl

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

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111394

Other (OTH) AF: 0.00 AC: 0 AN: 60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CEBALID syndrome Pathogenic:4 Other:1

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 -

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). -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Recurrent pathogenic variant in 9 out of 25 persons -

Feb 14, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:1

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) -

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

- -

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	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
PhyloP100		6.8
Vest4		0.82
GERP RS		3.4
Mutation Taster		=11/189	disease causing (ClinVar)

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

Other links and lift over

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