NM_033540.3:c.677G>A

Variant names:

• chr3-179365149-G-A
• rs143476739
• NM_033540.3:c.677G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.54
• Publications: 6 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012904614).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 1330 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.677G>A	p.Arg226Gln	missense	Exon 7 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.677G>A	p.Arg226Gln	missense	Exon 7 of 18	ENSP00000420617.1	Q8IWA4-1
	MFN1	ENST00000263969.9	TSL:1	c.677G>A	p.Arg226Gln	missense	Exon 6 of 17	ENSP00000263969.5	Q8IWA4-1
	MFN1	ENST00000474903.1	TSL:1	c.266G>A	p.Arg89Gln	missense	Exon 3 of 12	ENSP00000419926.1	H7C5H5

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 405 AN: 151910 Hom.: 3 Cov.: 32

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

GnomAD2 exomes AF: 0.00253 AC: 504 AN: 199284 AF XY: 0.00258

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 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.: 15 Cov.: 30 AF XY: 0.00192 AC XY: 1330 AN XY: 693602

African (AFR) AF: 0.00346 AC: 101 AN: 29174

American (AMR) AF: 0.00556 AC: 168 AN: 30194

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 326 AN: 24508

East Asian (EAS) AF: 0.000332 AC: 12 AN: 36104

South Asian (SAS) AF: 0.00146 AC: 108 AN: 73818

European-Finnish (FIN) AF: 0.000190 AC: 10 AN: 52622

Middle Eastern (MID) AF: 0.0282 AC: 152 AN: 5386

European-Non Finnish (NFE) AF: 0.00134 AC: 1454 AN: 1087934

Other (OTH) AF: 0.00421 AC: 242 AN: 57538

GnomAD4 genome AF: 0.00266 AC: 404 AN: 152020 Hom.: 3 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74322

African (AFR) AF: 0.00292 AC: 121 AN: 41478

American (AMR) AF: 0.00668 AC: 102 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 67982

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00260 Hom.: 7

Bravo AF: 0.00371

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.96
MPC		0.31
ClinPred		0.029	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.50
Mutation Taster		=99/1	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: rs143476739; hg19: chr3-179082937;