rs193920813

Variant names:

• chrX-130147601-G-A
• rs193920813
• NM_004208.4:c.497C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004208.4(AIFM1):​c.497C>T​(p.Pro166Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P166P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.15
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32564062).

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.497C>T	p.Pro166Leu	missense	Exon 5 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.485C>T	p.Pro162Leu	missense	Exon 5 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130847.4		c.497C>T	p.Pro166Leu	missense	Exon 5 of 17	NP_001124319.1	O95831-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.497C>T	p.Pro166Leu	missense	Exon 5 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.497C>T	p.Pro166Leu	missense	Exon 5 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.497C>T	p.Pro166Leu	missense	Exon 5 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098224 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363578

African (AFR) AF: 0.00 AC: 0 AN: 26402

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842118

Other (OTH) AF: 0.00 AC: 0 AN: 46098

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)
-	1	-	not provided (1)
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.00096	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Benign	0.79
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.38
Sift	Benign	0.72	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.32
MutPred		0.56		Loss of disorder (P = 0.015)
MVP		0.77
MPC		0.67
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.55
gMVP		0.86
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs193920813; hg19: chrX-129281576; COSMIC: COSV54858209; COSMIC: COSV54858209;