NM_033540.3:c.1345A>G

Variant names:

• chr3-179378356-A-G
• rs954391241
• NM_033540.3:c.1345A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033540.3(MFN1):​c.1345A>G​(p.Ile449Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. I449L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MFN1 NM_033540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81
• Publications: 0 publications found

Genes affected

MFN1 (HGNC:18262): (mitofusin 1) The protein encoded by this gene is a mediator of mitochondrial fusion. This protein and mitofusin 2 are homologs of the Drosophila protein fuzzy onion (Fzo). They are mitochondrial membrane proteins that interact with each other to facilitate mitochondrial targeting. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13864735).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033540.3. 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
	MFN1	NM_033540.3	MANE Select	c.1345A>G	p.Ile449Val	missense	Exon 13 of 18	NP_284941.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFN1	ENST00000471841.6	TSL:1 MANE Select	c.1345A>G	p.Ile449Val	missense	Exon 13 of 18	ENSP00000420617.1	Q8IWA4-1
	MFN1	ENST00000263969.9	TSL:1	c.1345A>G	p.Ile449Val	missense	Exon 12 of 17	ENSP00000263969.5	Q8IWA4-1
	MFN1	ENST00000474903.1	TSL:1	c.918+908A>G		intron	N/A	ENSP00000419926.1	H7C5H5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449152 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720558

African (AFR) AF: 0.00 AC: 0 AN: 32498

American (AMR) AF: 0.00 AC: 0 AN: 41292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 83066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108234

Other (OTH) AF: 0.0000167 AC: 1 AN: 59856

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.70
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.48	N
PhyloP100		2.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.30
Sift	Benign	0.88	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.22
MutPred		0.33		Gain of helix (P = 0.027)
MVP		0.66
MPC		0.14
ClinPred		0.15	T
GERP RS		5.3
Varity_R		0.10
gMVP		0.16
Mutation Taster		=76/24	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: rs954391241; hg19: chr3-179096144;