Genetic Variant MIEF1:p.Arg169Trp (chr22-39512414-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_019008.6(MIEF1):c.505C>T(p.Arg169Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00652 in 1,614,162 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0047 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0067 ( 41 hom. )

Consequence

MIEF1
NM_019008.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.12

Publications

15 publications found

Variant links:

Genes affected

MIEF1 (HGNC:25979): (mitochondrial elongation factor 1) Enables ADP binding activity; GDP binding activity; and identical protein binding activity. Involved in several processes, including positive regulation of mitochondrial fission; positive regulation of mitochondrial translation; and positive regulation of protein targeting to membrane. Located in mitochondrial matrix and mitochondrial outer membrane. Colocalizes with mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Apr 2022]

MIEF1 Gene-Disease associations (from GenCC):

optic atrophy 14
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

MIEF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007813871).

BP6

Variant 22-39512414-C-T is Benign according to our data. Variant chr22-39512414-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3249210.

BS2

High AC in GnomAd4 at 718 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019008.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MIEF1	NM_019008.6	MANE Select	c.505C>T	p.Arg169Trp	missense	Exon 5 of 6	NP_061881.2
MIEF1	NM_001304564.2		c.505C>T	p.Arg169Trp	missense	Exon 5 of 7	NP_001291493.1	B0QY95
MIEF1	NR_130789.2		n.906C>T		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MIEF1	ENST00000325301.7	TSL:1 MANE Select	c.505C>T	p.Arg169Trp	missense	Exon 5 of 6	ENSP00000327124.2	Q9NQG6-1
MIEF1	ENST00000402881.5	TSL:1	c.505C>T	p.Arg169Trp	missense	Exon 5 of 7	ENSP00000385110.1	B0QY95
MIEF1	ENST00000433117.6	TSL:1	n.419C>T		non_coding_transcript_exon	Exon 5 of 6	ENSP00000404096.2	Q9NQG6-2

Frequencies

GnomAD3 genomes

AF:

0.00472

AC:

718

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00758

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00489

AC:

1230

AN:

251308

AF XY:

0.00502

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00306

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00292

Gnomad NFE exome

AF:

0.00801

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00671

AC:

9814

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

4716

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33480

American (AMR)

AF:

0.00306

AC:

137

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00582

AC:

152

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39698

South Asian (SAS)

AF:

0.00108

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00262

AC:

140

AN:

53368

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00795

AC:

8839

AN:

1111986

Other (OTH)

AF:

0.00611

AC:

369

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

650

1300

1949

2599

3249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00471

AC:

718

AN:

152350

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41578

American (AMR)

AF:

0.00516

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00758

AC:

516

AN:

68030

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00653

Hom.:

Bravo

AF:

0.00459

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00513

AC:

623

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00867

EpiControl

AF:

0.00984

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.065

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.024

MetaRNN

Benign

0.0078

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.9

PhyloP100

3.1

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.3

REVEL

Benign

0.16

Sift

Benign

0.14

Sift4G

Uncertain

0.0030

Polyphen

0.14

Vest4

0.86

MVP

0.35

MPC

1.1

ClinPred

0.041

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.64

gMVP

0.70

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over