rs176708

Variant names:

• chrX-130143913-G-T
• rs176708
• NM_004208.4:c.696+1566C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004208.4(AIFM1):​c.696+1566C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 109,968 control chromosomes in the GnomAD database, including 10,291 homozygotes. There are 15,636 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (10291 hom., 15636 hem., cov: 22)
• Consequence: AIFM1 NM_004208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

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.696+1566C>A		intron	N/A	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.684+1566C>A		intron	N/A	NP_665811.1	O95831-3
	AIFM1	NM_001130847.4		c.696+1566C>A		intron	N/A	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.696+1566C>A		intron	N/A	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.696+1566C>A		intron	N/A	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.696+1566C>A		intron	N/A	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.491 AC: 53931 AN: 109919 Hom.: 10284 Cov.: 22

Gnomad AFR AF: 0.694

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.448

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.486

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.491 AC: 53974 AN: 109968 Hom.: 10291 Cov.: 22 AF XY: 0.484 AC XY: 15636 AN XY: 32306

African (AFR) AF: 0.693 AC: 20915 AN: 30163

American (AMR) AF: 0.460 AC: 4768 AN: 10355

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1322 AN: 2624

East Asian (EAS) AF: 0.191 AC: 669 AN: 3504

South Asian (SAS) AF: 0.474 AC: 1232 AN: 2601

European-Finnish (FIN) AF: 0.463 AC: 2620 AN: 5654

Middle Eastern (MID) AF: 0.452 AC: 94 AN: 208

European-Non Finnish (NFE) AF: 0.403 AC: 21221 AN: 52695

Other (OTH) AF: 0.487 AC: 726 AN: 1491

Alfa AF: 0.442 Hom.: 5170

Bravo AF: 0.499

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.21
DANN	Benign	0.41
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs176708; hg19: chrX-129277888;