chr22-27750975-C-T

Position:

• chr22-27750975-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_002430.3(MN1):​c.3903G>A​(p.Trp1301Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MN1 NM_002430.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 O:1
• Conservation: PhyloP100: 6.91

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 Uncertain_significance. Variant got 5 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. Fraction of 0.0151 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-27750975-C-T is Pathogenic according to our data. Variant chr22-27750975-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 809340.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Pathogenic=3}. Variant chr22-27750975-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MN1	NM_002430.3	c.3903G>A	p.Trp1301Ter	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.3903G>A	p.Trp1301Ter	stop_gained	2/2	1	NM_002430.3	ENSP00000304956	P1
MN1	ENST00000497225.1	n.259G>A		non_coding_transcript_exon_variant	2/2	1
MN1	ENST00000703102.1	n.428G>A		non_coding_transcript_exon_variant	2/2
MN1	ENST00000424656.1	c.258G>A	p.Trp86Ter	stop_gained, NMD_transcript_variant	2/3	5		ENSP00000397805

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CEBALID syndrome Pathogenic:3 Other:1

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 supporting). -
not provided, no classification provided	literature only	GeneReviews	-	Recurrent pathogenic variant in 3 out of 25 persons -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 02, 2023	- -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MN1: PM6:Strong, PM2, PS4:Moderate, PVS1:Moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2019	Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 31834374) -

Familial meningioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	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: rs1601319501; hg19: chr22-28146963; COSMIC: COSV56559175;