rs387906500

Variant names:

• chrX-130147492-CCTT-C
• rs387906500
• NM_004208.4:c.603_605delAAG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4_Supporting PP3_Moderate PP5

The NM_004208.4(AIFM1):​c.603_605delAAG​(p.Arg201del) variant causes a disruptive inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AIFM1 NM_004208.4 disruptive_inframe_deletion, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.46
• Publications: 20 publications found

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]

ENSG00000286650 (HGNC:):

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004208.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-130147492-CCTT-C is Pathogenic according to our data. Variant chrX-130147492-CCTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11546.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	NM_004208.4	MANE Select	c.603_605delAAG	p.Arg201del	disruptive_inframe_deletion splice_region	Exon 5 of 16	NP_004199.1
	AIFM1	NM_145812.3		c.591_593delAAG	p.Arg197del	disruptive_inframe_deletion splice_region	Exon 5 of 16	NP_665811.1
	AIFM1	NM_001130847.4		c.603_605delAAG	p.Arg201del	disruptive_inframe_deletion splice_region	Exon 5 of 17	NP_001124319.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.603_605delAAG	p.Arg201del	disruptive_inframe_deletion splice_region	Exon 5 of 16	ENSP00000287295.3
	AIFM1	ENST00000675092.1		c.603_605delAAG	p.Arg201del	disruptive_inframe_deletion splice_region	Exon 5 of 16	ENSP00000501772.1
	AIFM1	ENST00000319908.8	TSL:1	c.603_605delAAG	p.Arg201del	disruptive_inframe_deletion splice_region	Exon 5 of 16	ENSP00000315122.4

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 4
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906500; hg19: chrX-129281467;