rs1056740593

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004208.4(AIFM1):​c.1114G>A​(p.Val372Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000455 in 1,097,929 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

AIFM1
NM_004208.4 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3369722).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AIFM1NM_004208.4 linkuse as main transcriptc.1114G>A p.Val372Ile missense_variant 11/16 ENST00000287295.8 NP_004199.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AIFM1ENST00000287295.8 linkuse as main transcriptc.1114G>A p.Val372Ile missense_variant 11/161 NM_004208.4 ENSP00000287295 O95831-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
0.00000455
AC:
5
AN:
1097929
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
1
AN XY:
363287
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
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:
0.00000475
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 20, 2019The p.V372I variant (also known as c.1114G>A), located in coding exon 11 of the AIFM1 gene, results from a G to A substitution at nucleotide position 1114. The valine at codon 372 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 02, 2021- -
Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 17, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AIFM1 protein function. ClinVar contains an entry for this variant (Variation ID: 543931). This variant has not been reported in the literature in individuals affected with AIFM1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 372 of the AIFM1 protein (p.Val372Ile). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.011
T;.;.;T
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.83
T;T;T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.34
T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.6
.;.;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.73
N;N;N;N
REVEL
Benign
0.082
Sift
Benign
0.19
T;T;T;T
Sift4G
Benign
0.26
T;T;T;T
Polyphen
0.62, 0.77, 0.90
.;P;P;P
Vest4
0.25
MutPred
0.46
.;.;.;Gain of sheet (P = 0.0827);
MVP
0.64
MPC
0.71
ClinPred
0.88
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.61
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1056740593; hg19: chrX-129270668; COSMIC: COSV105153254; API