rs28501997

Variant names:

• chr22-27750782-A-G
• rs28501997
• NM_002430.3:c.*133T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002430.3(MN1):​c.*133T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 345,474 control chromosomes in the GnomAD database, including 603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (517 hom., cov: 23)
  • Exomes 𝑓: 0.033 (86 hom.)
• Consequence: MN1 NM_002430.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0310
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial meningioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 22-27750782-A-G is Benign according to our data. Variant chr22-27750782-A-G is described in ClinVar as Benign. ClinVar VariationId is 1276500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

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.*133T>C		3_prime_UTR	Exon 2 of 2	NP_002421.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MN1	ENST00000302326.5	TSL:1 MANE Select	c.*133T>C		3_prime_UTR	Exon 2 of 2	ENSP00000304956.4	Q10571
	MN1	ENST00000497225.1	TSL:1	n.452T>C		non_coding_transcript_exon	Exon 2 of 2
	MN1	ENST00000424656.1	TSL:5	n.*133T>C		non_coding_transcript_exon	Exon 2 of 3	ENSP00000397805.1	H7C105

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 6781 AN: 88458 Hom.: 513 Cov.: 23

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.000570

Gnomad EAS AF: 0.00305

Gnomad SAS AF: 0.00444

Gnomad FIN AF: 0.00158

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.00224

Gnomad OTH AF: 0.0480

GnomAD4 exome AF: 0.0333 AC: 8563 AN: 256990 Hom.: 86 Cov.: 6 AF XY: 0.0323 AC XY: 4165 AN XY: 128978

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

African (AFR) AF: 0.270 AC: 2000 AN: 7396

American (AMR) AF: 0.0607 AC: 314 AN: 5176

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 142 AN: 6112

East Asian (EAS) AF: 0.0129 AC: 210 AN: 16218

South Asian (SAS) AF: 0.0363 AC: 480 AN: 13218

European-Finnish (FIN) AF: 0.0255 AC: 415 AN: 16274

Middle Eastern (MID) AF: 0.0373 AC: 36 AN: 966

European-Non Finnish (NFE) AF: 0.0246 AC: 4391 AN: 178258

Other (OTH) AF: 0.0430 AC: 575 AN: 13372

⚠️ 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 AF: 0.0768 AC: 6792 AN: 88484 Hom.: 517 Cov.: 23 AF XY: 0.0736 AC XY: 3150 AN XY: 42780

African (AFR) AF: 0.253 AC: 6327 AN: 24984

American (AMR) AF: 0.0336 AC: 283 AN: 8416

Ashkenazi Jewish (ASJ) AF: 0.000570 AC: 1 AN: 1754

East Asian (EAS) AF: 0.00306 AC: 9 AN: 2938

South Asian (SAS) AF: 0.00444 AC: 14 AN: 3156

European-Finnish (FIN) AF: 0.00158 AC: 8 AN: 5068

Middle Eastern (MID) AF: 0.00641 AC: 1 AN: 156

European-Non Finnish (NFE) AF: 0.00224 AC: 90 AN: 40228

Other (OTH) AF: 0.0476 AC: 59 AN: 1240

Alfa AF: 0.226 Hom.: 4326

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.6
DANN	Benign	0.87
PhyloP100		0.031
Mutation Taster		=100/0	polymorphism

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: rs28501997; hg19: chr22-28146770; COSMIC: COSV56561117;