chrX-130129594-T-C

Variant names:

• chrX-130129594-T-C
• rs147206884
• NM_004208.4:c.1805A>G

Variant summary

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

The NM_004208.4(AIFM1):​c.1805A>G​(p.Asn602Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,097,611 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49
• Publications: 1 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 4 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.1805A>G	p.Asn602Ser	missense	Exon 16 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.1793A>G	p.Asn598Ser	missense	Exon 16 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130846.4		c.788A>G	p.Asn263Ser	missense	Exon 7 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.1805A>G	p.Asn602Ser	missense	Exon 16 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.1832A>G	p.Asn611Ser	missense	Exon 16 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.1799A>G	p.Asn600Ser	missense	Exon 16 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097611 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 4 AN XY: 362973

African (AFR) AF: 0.0000379 AC: 1 AN: 26389

American (AMR) AF: 0.00 AC: 0 AN: 35205

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54136

European-Finnish (FIN) AF: 0.000197 AC: 8 AN: 40531

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841555

Other (OTH) AF: 0.00 AC: 0 AN: 46075

GnomAD4 genome Cov.: 22

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.49	N
PhyloP100		7.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.15
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		0.056	B
Vest4		0.55
MVP		0.90
MPC		0.52
ClinPred		0.37	T
GERP RS		5.0
Varity_R		0.68
gMVP		0.91
Mutation Taster		=46/54	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: rs147206884; hg19: chrX-129263569;