3-179378630-A-T

Position:

• chr3-179378630-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033540.3(MFN1):​c.1478A>T​(p.His493Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MFN1 NM_033540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3581804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN1	NM_033540.3	c.1478A>T	p.His493Leu	missense_variant	14/18	ENST00000471841.6	NP_284941.2
MFN1	XM_005247596.5	c.1478A>T	p.His493Leu	missense_variant	14/18		XP_005247653.2
MFN1	XM_011512963.4	c.1037A>T	p.His346Leu	missense_variant	11/15		XP_011511265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN1	ENST00000471841.6	c.1478A>T	p.His493Leu	missense_variant	14/18	1	NM_033540.3	ENSP00000420617	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461290 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726918

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.1478A>T (p.H493L) alteration is located in exon 14 (coding exon 13) of the MFN1 gene. This alteration results from a A to T substitution at nucleotide position 1478, causing the histidine (H) at amino acid position 493 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.014
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.34	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.18	B;B
Vest4		0.53
MutPred		0.34		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.89
MPC		0.24
ClinPred		0.41	T
GERP RS		5.2
Varity_R		0.19
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs141316282; hg19: chr3-179096418;