rs12007545

Variant names:

• chrX-130137157-T-C
• rs12007545
• NM_004208.4:c.996A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-130137157-T-C
• chrX-130137157-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004208.4(AIFM1):​c.996A>G​(p.Gln332Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,208,827 control chromosomes in the GnomAD database, including 208 homozygotes. There are 2,328 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (100 hom., 804 hem., cov: 22)
  • Exomes 𝑓: 0.0041 (108 hom. 1524 hem.)
• Consequence: AIFM1 NM_004208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.203
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-130137157-T-C is Benign according to our data. Variant chrX-130137157-T-C is described in ClinVar as Benign. ClinVar VariationId is 136322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.203 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 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.996A>G	p.Gln332Gln	synonymous	Exon 10 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.984A>G	p.Gln328Gln	synonymous	Exon 10 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130846.4		c.-22A>G		5_prime_UTR	Exon 1 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.996A>G	p.Gln332Gln	synonymous	Exon 10 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.996A>G	p.Gln332Gln	synonymous	Exon 10 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.993A>G	p.Gln331Gln	synonymous	Exon 10 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 3118 AN: 110679 Hom.: 100 Cov.: 22

Gnomad AFR AF: 0.0930

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00152

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.000870

Gnomad OTH AF: 0.0223

GnomAD2 exomes AF: 0.00997 AC: 1827 AN: 183252 AF XY: 0.00811

Gnomad AFR exome AF: 0.0949

Gnomad AMR exome AF: 0.00609

Gnomad ASJ exome AF: 0.00174

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000904

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.00409 AC: 4492 AN: 1098095 Hom.: 108 Cov.: 31 AF XY: 0.00419 AC XY: 1524 AN XY: 363475

African (AFR) AF: 0.0941 AC: 2483 AN: 26400

American (AMR) AF: 0.00645 AC: 227 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 37 AN: 19386

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

South Asian (SAS) AF: 0.0150 AC: 814 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40395

Middle Eastern (MID) AF: 0.0169 AC: 70 AN: 4135

European-Non Finnish (NFE) AF: 0.000563 AC: 474 AN: 842125

Other (OTH) AF: 0.00840 AC: 387 AN: 46095

GnomAD4 genome AF: 0.0284 AC: 3143 AN: 110732 Hom.: 100 Cov.: 22 AF XY: 0.0243 AC XY: 804 AN XY: 33076

African (AFR) AF: 0.0936 AC: 2841 AN: 30348

American (AMR) AF: 0.0177 AC: 184 AN: 10401

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 4 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.0124 AC: 32 AN: 2576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5962

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.000870 AC: 46 AN: 52851

Other (OTH) AF: 0.0220 AC: 33 AN: 1502

Alfa AF: 0.00552 Hom.: 176

Bravo AF: 0.0332

EpiCase AF: 0.00224

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	not specified (1)
-	-	1	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.59
DANN	Benign	0.38
PhyloP100		0.20
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=298/2	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: rs12007545; hg19: chrX-129271132;