Variant 3-179368062-G-T 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.934G>T(p.Ala312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,572,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

MFN1
NM_033540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.108929604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MFN1	NM_033540.3 linkuse as main transcript	c.934G>T	p.Ala312Ser	missense_variant	9/18	ENST00000471841.6	NP_284941.2
MFN1	XM_005247596.5 linkuse as main transcript	c.934G>T	p.Ala312Ser	missense_variant	9/18		XP_005247653.2
MFN1	XM_011512963.4 linkuse as main transcript	c.493G>T	p.Ala165Ser	missense_variant	6/15		XP_011511265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN1	ENST00000471841.6 linkuse as main transcript	c.934G>T	p.Ala312Ser	missense_variant	9/18	1	NM_033540.3	ENSP00000420617	P1	Q8IWA4-1
MFN1	ENST00000263969.9 linkuse as main transcript	c.934G>T	p.Ala312Ser	missense_variant	8/17	1		ENSP00000263969	P1	Q8IWA4-1
MFN1	ENST00000474903.1 linkuse as main transcript	c.523G>T	p.Ala175Ser	missense_variant	5/12	1		ENSP00000419926
MFN1	ENST00000357390.8 linkuse as main transcript	c.934G>T	p.Ala312Ser	missense_variant, NMD_transcript_variant	9/17	2		ENSP00000349963		Q8IWA4-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000435

AC:

AN:

229624

Hom.:

AF XY:

0.00

AC XY:

AN XY:

125054

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:

0.00

Gnomad NFE exome

AF:

0.00000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000774

AC:

110

AN:

1420284

Hom.:

Cov.:

AF XY:

0.0000623

AC XY:

AN XY:

706480

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:

0.000100

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

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

Apr 13, 2022

The c.934G>T (p.A312S) alteration is located in exon 9 (coding exon 8) of the MFN1 gene. This alteration results from a G to T substitution at nucleotide position 934, causing the alanine (A) at amino acid position 312 to be replaced by a serine (S). 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

0.077

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.17

T;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.32

N;N;.

MutationTaster

Benign

0.83

N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.60

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.83

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.14

MutPred

0.27

Gain of disorder (P = 0.0378);Gain of disorder (P = 0.0378);.;

MVP

0.79

MPC

0.17

ClinPred

0.070

GERP RS

2.1

Varity_R

0.042

gMVP

0.095

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