rs769816388

Variant names:

• chrX-130131747-T-A
• rs769816388
• NM_004208.4:c.1501A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004208.4(AIFM1):​c.1501A>T​(p.Ser501Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,210,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S501N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 5 hem.)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.84
• Publications: 0 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_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 5 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.1501A>T	p.Ser501Cys	missense	Exon 14 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.1489A>T	p.Ser497Cys	missense	Exon 14 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130846.4		c.484A>T	p.Ser162Cys	missense	Exon 5 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.1501A>T	p.Ser501Cys	missense	Exon 14 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.1501A>T	p.Ser501Cys	missense	Exon 14 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.1495A>T	p.Ser499Cys	missense	Exon 14 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112567 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1097576 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 362952

African (AFR) AF: 0.00 AC: 0 AN: 26392

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54133

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 841525

Other (OTH) AF: 0.0000217 AC: 1 AN: 46071

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112567 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34727

African (AFR) AF: 0.00 AC: 0 AN: 31014

American (AMR) AF: 0.00 AC: 0 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3617

South Asian (SAS) AF: 0.00 AC: 0 AN: 2739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6199

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53307

Other (OTH) AF: 0.00 AC: 0 AN: 1516

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 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	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.014	D
Polyphen		0.39	B
Vest4		0.54
MutPred		0.49		Gain of catalytic residue at L502 (P = 0.0468)
MVP		0.92
MPC		0.67
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.94
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs769816388; hg19: chrX-129265722;