Genetic Variant AIFM1:p.Asn96Ser (chrX-130149531-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004208.4(AIFM1):c.287A>G(p.Asn96Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,209,346 control chromosomes in the GnomAD database, including 1 homozygotes. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000053 ( 1 hom. 32 hem. )

Consequence

AIFM1
NM_004208.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.29

Publications

0 publications found

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:

ENSG00000286650 (HGNC:):

ENSG00000286650 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.046139628).

BP6

Variant X-130149531-T-C is Benign according to our data. Variant chrX-130149531-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 239688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000529 (58/1097184) while in subpopulation MID AF = 0.00145 (6/4135). AF 95% confidence interval is 0.000631. There are 1 homozygotes in GnomAdExome4. There are 32 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 32 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIFM1	NM_004208.4	MANE Select	c.287A>G	p.Asn96Ser	missense	Exon 3 of 16	NP_004199.1
AIFM1	NM_145812.3		c.275A>G	p.Asn92Ser	missense	Exon 3 of 16	NP_665811.1
AIFM1	NM_001130847.4		c.287A>G	p.Asn96Ser	missense	Exon 3 of 17	NP_001124319.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.287A>G	p.Asn96Ser	missense	Exon 3 of 16	ENSP00000287295.3
AIFM1	ENST00000675092.1		c.287A>G	p.Asn96Ser	missense	Exon 3 of 16	ENSP00000501772.1
AIFM1	ENST00000319908.8	TSL:1	c.287A>G	p.Asn96Ser	missense	Exon 3 of 16	ENSP00000315122.4

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000764

AC:

AN:

183360

AF XY:

0.0000885

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000529

AC:

AN:

1097184

Hom.:

Cov.:

AF XY:

0.0000883

AC XY:

AN XY:

362576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26372

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.000758

AC:

AN:

54117

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40420

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000951

AC:

AN:

841304

Other (OTH)

AF:

0.0000651

AC:

AN:

46063

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112162

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30806

American (AMR)

AF:

0.00

AC:

AN:

10525

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3622

South Asian (SAS)

AF:

0.00

AC:

AN:

2726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6109

Middle Eastern (MID)

AF:

0.00424

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53285

Other (OTH)

AF:

0.00

AC:

AN:

1514

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jun 21, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided

Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AIFM1: BP4, BS2

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

M_CAP

Benign

0.018

MetaRNN

Benign

0.046

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.8

PhyloP100

2.3

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.34

REVEL

Benign

0.12

Sift

Benign

0.52

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.12

MutPred

0.39

Gain of phosphorylation at N96 (P = 0.007)

MVP

0.67

MPC

0.51

ClinPred

0.032

GERP RS

4.3

Varity_R

0.070

gMVP

0.54

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over