Genetic Variant AIFM1:p.Met1? (chrX-130137134-A-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001130846.4(AIFM1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 22)

Consequence

AIFM1
NM_001130846.4 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 8.73

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 14 codons. Genomic position: 130137096. Lost 0.048 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-130137134-A-G is Pathogenic according to our data. Variant chrX-130137134-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130846.4. 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.1019T>C	p.Met340Thr	missense	Exon 10 of 16	NP_004199.1
AIFM1	NM_001130846.4		c.2T>C	p.Met1?	start_lost	Exon 1 of 7	NP_001124318.2
AIFM1	NM_145812.3		c.1007T>C	p.Met336Thr	missense	Exon 10 of 16	NP_665811.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIFM1	ENST00000460436.6	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENSP00000431222.1
AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.1019T>C	p.Met340Thr	missense	Exon 10 of 16	ENSP00000287295.3
AIFM1	ENST00000675092.1		c.1019T>C	p.Met340Thr	missense	Exon 10 of 16	ENSP00000501772.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease X-linked recessive 4 (2)

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)

not provided (1)

Pes planus;C0018784:Sensorineural hearing loss disorder;C0427065:Distal muscle weakness;C1866141:Foot dorsiflexor weakness (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.4

PhyloP100

8.7

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.87

MutPred

0.80

Loss of stability (P = 0.0414)

MVP

0.97

MPC

1.8

ClinPred

1.0

GERP RS

5.2

PromoterAI

0.072

Neutral

(source)

Varity_R

0.98

gMVP

0.99

Mutation Taster

=19/181

disease causing (ClinVar)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over