Genetic Variant AIFM1:p.Gln332His (chrX-130137157-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_004208.4(AIFM1):c.996A>C(p.Gln332His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q332E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

AIFM1
NM_004208.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.203

Publications

3 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:

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:

ENSG00000286650 (HGNC:):

ENSG00000286650 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_004208.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

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	UniProt
AIFM1	NM_004208.4	MANE Select	c.996A>C	p.Gln332His	missense	Exon 10 of 16	NP_004199.1	O95831-1
AIFM1	NM_145812.3		c.984A>C	p.Gln328His	missense	Exon 10 of 16	NP_665811.1	O95831-3
AIFM1	NM_001130846.4		c.-22A>C		5_prime_UTR	Exon 1 of 7	NP_001124318.2	E9PMA0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.996A>C	p.Gln332His	missense	Exon 10 of 16	ENSP00000287295.3	O95831-1
AIFM1	ENST00000675092.1		c.996A>C	p.Gln332His	missense	Exon 10 of 16	ENSP00000501772.1	A0A6Q8PFE1
AIFM1	ENST00000319908.8	TSL:1	c.993A>C	p.Gln331His	missense	Exon 10 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

176

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.056

MutationAssessor

Uncertain

2.8

PhyloP100

0.20

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.63

Sift

Benign

0.081

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.74

MutPred

0.61

Loss of methylation at K337 (P = 0.1492)

MVP

0.98

MPC

1.1

ClinPred

0.99

GERP RS

-1.4

PromoterAI

0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.94

Mutation Taster

=18/82

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over