Variant NM_033540.3:c.677G>A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_033540.3(MFN1):c.677G>A(p.Arg226Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00192 in 1,549,298 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 15 hom. )

Consequence

MFN1
NM_033540.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 6.54

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012904614).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00184 (2573/1397278) while in subpopulation MID AF= 0.0282 (152/5386). AF 95% confidence interval is 0.0246. There are 15 homozygotes in gnomad4_exome. There are 1330 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFN1	NM_033540.3 link	c.677G>A	p.Arg226Gln	missense_variant	Exon 7 of 18	ENST00000471841.6	NP_284941.2	Q8IWA4-1
MFN1	XM_005247596.5 link	c.677G>A	p.Arg226Gln	missense_variant	Exon 7 of 18		XP_005247653.2	Q8IWA4-1
MFN1	XM_011512963.4 link	c.236G>A	p.Arg79Gln	missense_variant	Exon 4 of 15		XP_011511265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFN1	ENST00000471841.6 link	c.677G>A	p.Arg226Gln	missense_variant	Exon 7 of 18	1	NM_033540.3	ENSP00000420617.1		Q8IWA4-1

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

405

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00669

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00253

AC:

504

AN:

199284

Hom.:

AF XY:

0.00258

AC XY:

282

AN XY:

109402

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00462

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00141

Gnomad FIN exome

AF:

0.0000959

Gnomad NFE exome

AF:

0.00181

Gnomad OTH exome

AF:

0.00649

GnomAD4 exome

AF:

0.00184

AC:

2573

AN:

1397278

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1330

AN XY:

693602

show subpopulations

Gnomad4 AFR exome

AF:

0.00346

Gnomad4 AMR exome

AF:

0.00556

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.000332

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.000190

Gnomad4 NFE exome

AF:

0.00134

Gnomad4 OTH exome

AF:

0.00421

GnomAD4 genome

AF:

0.00266

AC:

404

AN:

152020

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00292

Gnomad4 AMR

AF:

0.00668

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00150

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00299

Hom.:

Bravo

AF:

0.00371

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00249

AC:

302

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

D;D;.;.

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;D;D

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.2

M;M;.;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.1

N;N;D;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.024

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.56

MVP

0.96

MPC

0.31

ClinPred

0.029

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.50

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