Variant 3-179378356-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MFN1
NM_033540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81

Variant links:

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]

MFN1 links:

MFN1 (HGNC:):

MFN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13864735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN1	NM_033540.3 linkuse as main transcript	c.1345A>G	p.Ile449Val	missense_variant	13/18	ENST00000471841.6	NP_284941.2	Q8IWA4-1
MFN1	XM_005247596.5 linkuse as main transcript	c.1345A>G	p.Ile449Val	missense_variant	13/18		XP_005247653.2	Q8IWA4-1
MFN1	XM_011512963.4 linkuse as main transcript	c.904A>G	p.Ile302Val	missense_variant	10/15		XP_011511265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN1	ENST00000471841.6 linkuse as main transcript	c.1345A>G	p.Ile449Val	missense_variant	13/18	1	NM_033540.3	ENSP00000420617.1		Q8IWA4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720558

show subpopulations

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:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.1345A>G (p.I449V) alteration is located in exon 13 (coding exon 12) of the MFN1 gene. This alteration results from a A to G substitution at nucleotide position 1345, causing the isoleucine (I) at amino acid position 449 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

.;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.48

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.070

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.88

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0020

B;B

Vest4

0.22

MutPred

0.33

Gain of helix (P = 0.027);Gain of helix (P = 0.027);

MVP

0.66

MPC

0.14

ClinPred

0.15

GERP RS

5.3

Varity_R

0.10

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over