rs724160021

Variant names:

• chrX-130136085-C-T
• rs724160021
• NM_004208.4:c.1265G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 12P and 4B. PM5 PP3_Moderate PP5_Very_Strong BS2

The NM_004208.4(AIFM1):​c.1265G>A​(p.Arg422Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,098,201 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R422W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.57
• Publications: 14 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]

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]

ENSG00000286650 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-130136086-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-130136085-C-T is Pathogenic according to our data. Variant chrX-130136085-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	NM_004208.4	MANE Select	c.1265G>A	p.Arg422Gln	missense	Exon 12 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.1253G>A	p.Arg418Gln	missense	Exon 12 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130846.4		c.248G>A	p.Arg83Gln	missense	Exon 3 of 7	NP_001124318.2	E9PMA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.1265G>A	p.Arg422Gln	missense	Exon 12 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.1265G>A	p.Arg422Gln	missense	Exon 12 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.1262G>A	p.Arg421Gln	missense	Exon 12 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000637 AC: 7 AN: 1098201 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 2 AN XY: 363555

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000831 AC: 7 AN: 842102

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome Cov.: 22

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Deafness, X-linked 5 (3)
1	-	-	Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)
1	-	-	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.37	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.52		Loss of methylation at R422 (P = 0.018)
MVP		0.92
MPC		1.7
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: -1

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

Other links and lift over

dbSNP: rs724160021; hg19: chrX-129270060;