rs12014115

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004208.4(AIFM1):c.918C>T(p.Ile306Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,208,481 control chromosomes in the GnomAD database, including 208 homozygotes. There are 3,170 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 97 hom., 831 hem., cov: 22)

Exomes 𝑓: 0.0064 ( 111 hom. 2339 hem. )

Consequence

AIFM1
NM_004208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.228

Publications

3 publications found

Variant links:

Genes affected

AIFM1 (HGNC:8768): (apoptosis inducing factor mitochondria associated 1) This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells, and it is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the translocation of this protein to the nucleus where it affects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Mutations in this gene cause combined oxidative phosphorylation deficiency 6 (COXPD6), a severe mitochondrial encephalomyopathy, as well as Cowchock syndrome, also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX-4), a disorder resulting in neuropathy, and axonal and motor-sensory defects with deafness and cognitive disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 10. [provided by RefSeq, Aug 2015]

AIFM1 links:

ENSG00000286650 (HGNC:):

ENSG00000286650 links:

RAB33A (HGNC:9773): (RAB33A, member RAS oncogene family) The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. It is GTP-binding protein and may be involved in vesicle transport. [provided by RefSeq, Jul 2008]

RAB33A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant X-130138642-G-A is Benign according to our data. Variant chrX-130138642-G-A is described in ClinVar as [Benign]. Clinvar id is 136320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.228 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIFM1	NM_004208.4 link	c.918C>T	p.Ile306Ile	synonymous_variant	Exon 9 of 16	ENST00000287295.8	NP_004199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIFM1	ENST00000287295.8 link	c.918C>T	p.Ile306Ile	synonymous_variant	Exon 9 of 16	1	NM_004208.4	ENSP00000287295.3		O95831-1
AIFM1	ENST00000675092.1 link	c.918C>T	p.Ile306Ile	synonymous_variant	Exon 9 of 16			ENSP00000501772.1		A0A6Q8PFE1

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

3276

AN:

110911

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0924

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.00227

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0129

Gnomad FIN

AF:

0.000683

Gnomad MID

AF:

0.0168

Gnomad NFE

AF:

0.00370

Gnomad OTH

AF:

0.0243

GnomAD2 exomes

AF:

0.0114

AC:

2088

AN:

183414

AF XY:

0.00940

show subpopulations

Gnomad AFR exome

AF:

0.0951

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.00187

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00107

Gnomad NFE exome

AF:

0.00358

Gnomad OTH exome

AF:

0.00861

GnomAD4 exome

AF:

0.00639

AC:

7015

AN:

1097515

Hom.:

111

Cov.:

AF XY:

0.00645

AC XY:

2339

AN XY:

362897

show subpopulations

African (AFR)

AF:

0.0941

AC:

2482

AN:

26374

American (AMR)

AF:

0.00676

AC:

238

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00201

AC:

AN:

19380

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30200

South Asian (SAS)

AF:

0.0154

AC:

833

AN:

54130

European-Finnish (FIN)

AF:

0.000865

AC:

AN:

40484

Middle Eastern (MID)

AF:

0.0184

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00339

AC:

2852

AN:

841536

Other (OTH)

AF:

0.00996

AC:

459

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

247

494

742

989

1236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0297

AC:

3301

AN:

110966

Hom.:

Cov.:

AF XY:

0.0250

AC XY:

831

AN XY:

33208

show subpopulations

African (AFR)

AF:

0.0930

AC:

2836

AN:

30486

American (AMR)

AF:

0.0178

AC:

186

AN:

10439

Ashkenazi Jewish (ASJ)

AF:

0.00227

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.0130

AC:

AN:

2623

European-Finnish (FIN)

AF:

0.000683

AC:

AN:

5856

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00370

AC:

196

AN:

52979

Other (OTH)

AF:

0.0240

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

111

222

334

445

556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0147

Hom.:

173

Bravo

AF:

0.0346

EpiCase

AF:

0.00551

EpiControl

AF:

0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 30, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 20, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Severe X-linked mitochondrial encephalomyopathy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.71

(source)

DANN

Benign

0.80

PhyloP100

-0.23

Mutation Taster

=99/1

polymorphism (auto)

(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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rs12014115

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over