rs873457

Variant names:

• chr1-11986277-C-G
• rs873457
• NM_014874.4:c.-4-2888C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014874.4(MFN2):​c.-4-2888C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 152,052 control chromosomes in the GnomAD database, including 29,877 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29877 hom., cov: 32)
• Consequence: MFN2 NM_014874.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 16 publications found

Genes affected

MFN2 (HGNC:16877): (mitofusin 2) This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

MFN2 Gene-Disease associations (from GenCC):

• neuropathy, hereditary motor and sensory, type 6A

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• axonal hereditary motor and sensory neuropathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2A2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary motor and sensory neuropathy type 6

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multiple symmetric lipomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-onset axonal neuropathy due to MFN2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014874.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	NM_014874.4	MANE Select	c.-4-2888C>G		intron	N/A	NP_055689.1
	MFN2	NM_001127660.2		c.-4-2888C>G		intron	N/A	NP_001121132.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN2	ENST00000235329.10	TSL:1 MANE Select	c.-4-2888C>G		intron	N/A	ENSP00000235329.5
	MFN2	ENST00000675298.1		c.-4-2888C>G		intron	N/A	ENSP00000501839.1
	MFN2	ENST00000675817.1		c.-4-2888C>G		intron	N/A	ENSP00000502422.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94680 AN: 151934 Hom.: 29867 Cov.: 32

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.608

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.623 AC: 94733 AN: 152052 Hom.: 29877 Cov.: 32 AF XY: 0.625 AC XY: 46451 AN XY: 74314

African (AFR) AF: 0.596 AC: 24680 AN: 41442

American (AMR) AF: 0.533 AC: 8145 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1682 AN: 3472

East Asian (EAS) AF: 0.638 AC: 3293 AN: 5160

South Asian (SAS) AF: 0.682 AC: 3282 AN: 4812

European-Finnish (FIN) AF: 0.736 AC: 7790 AN: 10584

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.647 AC: 43980 AN: 67990

Other (OTH) AF: 0.607 AC: 1283 AN: 2114

Alfa AF: 0.631 Hom.: 3805

Bravo AF: 0.603

Asia WGS AF: 0.661 AC: 2298 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.48
DANN	Benign	0.45
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs873457; hg19: chr1-12046334;