chr22-27750995-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1_StrongPS3PM2PP5

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). ClinVar reports functional evidence for this variant: "SCV000244234: 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. Miyake, 2020".

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:9U:1O:1

Conservation

PhyloP100: 6.81

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

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

MN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000244234: 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. Miyake, 2020

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002430.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MN1	NM_002430.3	MANE Select	c.3883C>T	p.Arg1295*	stop_gained	Exon 2 of 2	NP_002421.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MN1	ENST00000302326.5	TSL:1 MANE Select	c.3883C>T	p.Arg1295*	stop_gained	Exon 2 of 2	ENSP00000304956.4	Q10571
MN1	ENST00000497225.1	TSL:1	n.239C>T		non_coding_transcript_exon	Exon 2 of 2
MN1	ENST00000424656.1	TSL:5	n.235C>T		non_coding_transcript_exon	Exon 2 of 3	ENSP00000397805.1	H7C105

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

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

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111394

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

CEBALID syndrome (6)

not provided (3)

Inborn genetic diseases (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

PhyloP100

6.8

Vest4

0.82

GERP RS

3.4

Mutation Taster

=11/189

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over