X-130129963-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004208.4(AIFM1):​c.1770+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,209,543 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.000020 ( 0 hom. 3 hem. )

Consequence

AIFM1
NM_004208.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00002453
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.18
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 Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant X-130129963-C-A is Benign according to our data. Variant chrX-130129963-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1930800.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AIFM1NM_004208.4 linkuse as main transcriptc.1770+7G>T splice_region_variant, intron_variant ENST00000287295.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AIFM1ENST00000287295.8 linkuse as main transcriptc.1770+7G>T splice_region_variant, intron_variant 1 NM_004208.4 O95831-1

Frequencies

GnomAD3 genomes
AF:
0.0000268
AC:
3
AN:
112096
Hom.:
0
Cov.:
22
AF XY:
0.0000292
AC XY:
1
AN XY:
34250
show subpopulations
Gnomad AFR
AF:
0.0000648
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000950
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000546
AC:
1
AN:
183008
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
67542
show subpopulations
Gnomad AFR exome
AF:
0.0000760
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000200
AC:
22
AN:
1097447
Hom.:
0
Cov.:
31
AF XY:
0.00000827
AC XY:
3
AN XY:
362809
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:
0.0000250
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000268
AC:
3
AN:
112096
Hom.:
0
Cov.:
22
AF XY:
0.0000292
AC XY:
1
AN XY:
34250
show subpopulations
Gnomad4 AFR
AF:
0.0000648
Gnomad4 AMR
AF:
0.0000950
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJun 30, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
0.33
DANN
Benign
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000025
dbscSNV1_RF
Benign
0.0
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: rs750502653; hg19: chrX-129263938; API