rs12007545

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000287295.8(AIFM1):c.996A>G(p.Gln332=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,208,827 control chromosomes in the GnomAD database, including 208 homozygotes. There are 2,328 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 100 hom., 804 hem., cov: 22)

Exomes 𝑓: 0.0041 ( 108 hom. 1524 hem. )

Consequence

AIFM1
ENST00000287295.8 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.203

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:):

RAB33A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant X-130137157-T-C is Benign according to our data. Variant chrX-130137157-T-C is described in ClinVar as [Benign]. Clinvar id is 136322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-130137157-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.203 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 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.996A>G	p.Gln332=	synonymous_variant	10/16	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.996A>G	p.Gln332=	synonymous_variant	10/16	1	NM_004208.4	ENSP00000287295		O95831-1

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

3118

AN:

110679

Hom.:

100

Cov.:

AF XY:

0.0237

AC XY:

781

AN XY:

33013

show subpopulations

Gnomad AFR

AF:

0.0930

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.00152

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0167

Gnomad NFE

AF:

0.000870

Gnomad OTH

AF:

0.0223

GnomAD3 exomes

AF:

0.00997

AC:

1827

AN:

183252

Hom.:

AF XY:

0.00811

AC XY:

549

AN XY:

67708

show subpopulations

Gnomad AFR exome

AF:

0.0949

Gnomad AMR exome

AF:

0.00609

Gnomad ASJ exome

AF:

0.00174

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000904

Gnomad OTH exome

AF:

0.00772

GnomAD4 exome

AF:

0.00409

AC:

4492

AN:

1098095

Hom.:

108

Cov.:

AF XY:

0.00419

AC XY:

1524

AN XY:

363475

show subpopulations

Gnomad4 AFR exome

AF:

0.0941

Gnomad4 AMR exome

AF:

0.00645

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0150

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000563

Gnomad4 OTH exome

AF:

0.00840

GnomAD4 genome

AF:

0.0284

AC:

3143

AN:

110732

Hom.:

100

Cov.:

AF XY:

0.0243

AC XY:

804

AN XY:

33076

show subpopulations

Gnomad4 AFR

AF:

0.0936

Gnomad4 AMR

AF:

0.0177

Gnomad4 ASJ

AF:

0.00152

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000870

Gnomad4 OTH

AF:

0.0220

Alfa

AF:

0.00452

Hom.:

129

Bravo

AF:

0.0332

EpiCase

AF:

0.00224

EpiControl

AF:

0.00148

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	- -

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. -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Severe X-linked mitochondrial encephalomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

-0.58

CADD

Benign

0.59

DANN

Benign

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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