rs768648610

Variant names:

• chrX-130129605-A-C
• rs768648610
• NM_004208.4:c.1794T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-130129605-A-C
• chrX-130129605-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004208.4(AIFM1):​c.1794T>G​(p.His598Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.359

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIFM1	NM_004208.4	c.1794T>G	p.His598Gln	missense_variant	Exon 16 of 16	ENST00000287295.8	NP_004199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIFM1	ENST00000287295.8	c.1794T>G	p.His598Gln	missense_variant	Exon 16 of 16	1	NM_004208.4	ENSP00000287295.3
AIFM1	ENST00000675092.1	c.1821T>G	p.His607Gln	missense_variant	Exon 16 of 16			ENSP00000501772.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;.;.;T
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	0.064	D
MutationAssessor	Benign	1.6	.;.;.;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.054	T;D;D;D
Sift4G	Benign	0.084	T;T;D;T
Polyphen		0.93, 1.0, 0.99	.;P;D;D
Vest4		0.60
MutPred		0.27		.;.;.;Gain of ubiquitination at K593 (P = 0.0651);
MVP		0.96
MPC		1.3
ClinPred		0.98	D
GERP RS		1.2
Varity_R		0.89
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs768648610; hg19: chrX-129263580;