Variant 3-179358949-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_033540.3(MFN1):c.358G>A(p.Gly120Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.000017 ( 0 hom. )

Consequence

MFN1
NM_033540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN1	NM_033540.3 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	4/18	ENST00000471841.6	NP_284941.2	Q8IWA4-1
MFN1	XM_005247596.5 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	4/18		XP_005247653.2	Q8IWA4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MFN1	ENST00000471841.6 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	4/18	1	NM_033540.3	ENSP00000420617.1	Q8IWA4-1
MFN1	ENST00000263969.9 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	3/17	1		ENSP00000263969.5	Q8IWA4-1
MFN1	ENST00000467174.6 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	4/5	4		ENSP00000419134.2	C9JXQ1
MFN1	ENST00000357390.8 linkuse as main transcript	n.358G>A		non_coding_transcript_exon_variant	4/17	2		ENSP00000349963.4	Q8IWA4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251372

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000749

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Dec 07, 2024

The c.358G>A (p.G120R) alteration is located in exon 4 (coding exon 3) of the MFN1 gene. This alteration results from a G to A substitution at nucleotide position 358, causing the glycine (G) at amino acid position 120 to be replaced by an arginine (R). 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

0.18

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.40

N;.;N

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.69

Sift

Benign

0.044

D;T;D

Sift4G

Uncertain

0.042

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.45

MutPred

0.49

Gain of phosphorylation at T118 (P = 0.0918);Gain of phosphorylation at T118 (P = 0.0918);Gain of phosphorylation at T118 (P = 0.0918);

MVP

0.96

MPC

0.73

ClinPred

0.82

GERP RS

5.9

Varity_R

0.53

gMVP

0.70

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