rs1553140991

Positions:

• chr1-11989259-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000235329.10(MFN2):​c.91C>T​(p.His31Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H31Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MFN2 ENST00000235329.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MFN2. . Gene score misZ 1.6575 (greater than the threshold 3.09). Trascript score misZ 3.2174 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, hereditary motor and sensory neuropathy type 6, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, severe early-onset axonal neuropathy due to MFN2 deficiency.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.91C>T	p.His31Tyr	missense_variant	3/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.91C>T	p.His31Tyr	missense_variant	3/19	1	NM_014874.4	ENSP00000235329	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2020

In summary, this variant has uncertain impact on MFN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with a MFN2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with tyrosine at codon 31 of the MFN2 protein (p.His31Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.9	N;N;D
REVEL	Pathogenic	0.66
Sift	Benign	0.069	T;T;D
Sift4G	Benign	0.10	T;T;D
Polyphen		0.99	D;D;.
Vest4		0.85
MutPred		0.34		Loss of disorder (P = 0.0581);Loss of disorder (P = 0.0581);Loss of disorder (P = 0.0581);
MVP		0.92
MPC		1.7
ClinPred		0.95	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.67

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: rs1553140991; hg19: chr1-12049316;