rs144860227

Positions:

• chr1-12009668-G-A
• chr1-12009668-G-C
• chr1-12009668-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Strong

The NM_014874.4(MFN2):​c.2146G>A​(p.Ala716Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,614,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A716P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:3
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014874.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MFN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.033519685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFN2	NM_014874.4	c.2146G>A	p.Ala716Thr	missense_variant	18/19	ENST00000235329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFN2	ENST00000235329.10	c.2146G>A	p.Ala716Thr	missense_variant	18/19	1	NM_014874.4	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251490 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135922

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000259 AC: 378 AN: 1461884 Hom.: 1 Cov.: 32 AF XY: 0.000249 AC XY: 181 AN XY: 727248

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74480

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	This variant is associated with the following publications: (PMID: 29361379, 29341354, 20350294, 23106488, 21508331, 22492563, 20482598) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MFN2: PM1, PM2:Supporting, BP4 -

Charcot-Marie-Tooth disease Pathogenic:1 Uncertain:1

Likely pathogenic, flagged submission	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

Charcot-Marie-Tooth disease type 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 716 of the MFN2 protein (p.Ala716Thr). This variant is present in population databases (rs144860227, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of MFN2-related conditions (PMID: 20350294, 21508331, 22492563, 33415332). ClinVar contains an entry for this variant (Variation ID: 214649). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MFN2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2022

The p.A716T variant (also known as c.2146G>A), located in coding exon 16 of the MFN2 gene, results from a G to A substitution at nucleotide position 2146. The alanine at codon 716 is replaced by threonine, an amino acid with similar properties. This variant was reported to segregate with dominant intermediate Charcot Marie Tooth disease in a single family (Braathen GJ et al. BMC Med. Genet., 2010 Mar;11:48) and has also been reported in two individuals affected with Charcot Marie Tooth disease type 2 (Feely SM et al. Neurology, 2011 May;76:1690-6; Sitarz KS et al. Brain, 2012 Aug;135:e219, 1-3; author reply e220, 1-3). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of Charcot-Marie-Tooth disease (CMT) type 2A2A and hereditary motor and sensory neuropathy VIA; however, its contribution to the development of Charcot-Marie-Tooth disease (CMT) type 2A2B is uncertain. -

Hereditary motor and sensory neuropathy with optic atrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.57	T;.
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.034	T;T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Benign	-0.14	N;N
MutationTaster	Benign	0.79	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.61	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.54	P;P
Vest4		0.44
MVP		0.59
MPC		0.20
ClinPred		0.023	T
GERP RS		3.4
Varity_R		0.024
gMVP		0.25

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: rs144860227; hg19: chr1-12069725;