rs12014115

Positions:

chrX-130138642-G-A

Variant summary

Our verdict is Benign. Variant got -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

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:

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:

AIFM1 (HGNC:):

AIFM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chrX-130138642-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
AIFM1	NM_004208.4 linkuse as main transcript	c.918C>T	p.Ile306Ile	synonymous_variant	9/16	ENST00000287295.8	NP_004199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIFM1	ENST00000287295.8 linkuse as main transcript	c.918C>T	p.Ile306Ile	synonymous_variant	9/16	1	NM_004208.4	ENSP00000287295.3		O95831-1
AIFM1	ENST00000675092.1 linkuse as main transcript	c.918C>T	p.Ile306Ile	synonymous_variant	9/16			ENSP00000501772.1		A0A6Q8PFE1

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

3276

AN:

110911

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

808

AN XY:

33143

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

GnomAD3 exomes

AF:

0.0114

AC:

2088

AN:

183414

Hom.:

AF XY:

0.00940

AC XY:

638

AN XY:

67850

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 SAS exome

AF:

0.0155

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

Gnomad4 AFR exome

AF:

0.0941

Gnomad4 AMR exome

AF:

0.00676

Gnomad4 ASJ exome

AF:

0.00201

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0154

Gnomad4 FIN exome

AF:

0.000865

Gnomad4 NFE exome

AF:

0.00339

Gnomad4 OTH exome

AF:

0.00996

GnomAD4 genome

AF:

0.0297

AC:

3301

AN:

110966

Hom.:

Cov.:

AF XY:

0.0250

AC XY:

831

AN XY:

33208

show subpopulations

Gnomad4 AFR

AF:

0.0930

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.00227

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0130

Gnomad4 FIN

AF:

0.000683

Gnomad4 NFE

AF:

0.00370

Gnomad4 OTH

AF:

0.0240

Alfa

AF:

0.0147

Hom.:

153

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 11, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2013

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.71

DANN

Benign

0.80

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