X-130129594-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004208.4(AIFM1):ā€‹c.1805A>Gā€‹(p.Asn602Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,097,611 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 22)
Exomes š‘“: 0.000010 ( 0 hom. 4 hem. )

Consequence

AIFM1
NM_004208.4 missense

Scores

1
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AIFM1NM_004208.4 linkuse as main transcriptc.1805A>G p.Asn602Ser missense_variant 16/16 ENST00000287295.8 NP_004199.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AIFM1ENST00000287295.8 linkuse as main transcriptc.1805A>G p.Asn602Ser missense_variant 16/161 NM_004208.4 ENSP00000287295 O95831-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
0.0000100
AC:
11
AN:
1097611
Hom.:
0
Cov.:
29
AF XY:
0.0000110
AC XY:
4
AN XY:
362973
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:
0.000197
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 22, 2020In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with AIFM1-related conditions. This variant is present in population databases (rs147206884, ExAC 0.002%). This sequence change replaces asparagine with serine at codon 602 of the AIFM1 protein (p.Asn602Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.067
T;.;.;T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.45
T;T;T;T
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
0.49
.;.;.;N
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.0
D;D;D;D
REVEL
Benign
0.15
Sift
Benign
0.15
T;T;T;T
Sift4G
Benign
0.24
T;T;T;T
Polyphen
0.056, 0.22, 0.26
.;B;B;B
Vest4
0.55
MVP
0.90
MPC
0.52
ClinPred
0.37
T
GERP RS
5.0
Varity_R
0.68
gMVP
0.91

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.

Other links and lift over

dbSNP: rs147206884; hg19: chrX-129263569; API