rs954391241

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-179378356-A-C
• chr3-179378356-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033540.3(MFN1):​c.1345A>C​(p.Ile449Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. I449V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29466295).

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>C	p.Ile449Leu	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>C	p.Ile449Leu	missense	Exon 13 of 18	ENSP00000420617.1	Q8IWA4-1
	MFN1	ENST00000263969.9	TSL:1	c.1345A>C	p.Ile449Leu	missense	Exon 12 of 17	ENSP00000263969.5	Q8IWA4-1
	MFN1	ENST00000474903.1	TSL:1	c.918+908A>C		intron	N/A	ENSP00000419926.1	H7C5H5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	0.12
BayesDel_addAF	Benign	0.00085	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.28
Sift	Benign	0.067	T
Sift4G	Benign	0.073	T
Polyphen		0.0020	B
Vest4		0.44
MutPred		0.39		Gain of helix (P = 0.027)
MVP		0.74
MPC		0.17
ClinPred		0.49	T
GERP RS		5.3
Varity_R		0.25
gMVP		0.46
Mutation Taster		=69/31	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;