NM_004208.4:c.918C>T

Variant names:

• chrX-130138642-G-A
• rs12014115
• NM_004208.4:c.918C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004208.4(AIFM1):​c.918C>T​(p.Ile306Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,208,481 control chromosomes in the GnomAD database, including 208 homozygotes. There are 3,170 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I306I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (97 hom., 831 hem., cov: 22)
  • Exomes 𝑓: 0.0064 (111 hom. 2339 hem.)
• Consequence: AIFM1 NM_004208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.228
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-130138642-G-A is Benign according to our data. Variant chrX-130138642-G-A is described in ClinVar as Benign. ClinVar VariationId is 136320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.228 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0902 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.918C>T	p.Ile306Ile	synonymous	Exon 9 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.906C>T	p.Ile302Ile	synonymous	Exon 9 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130847.4		c.918C>T	p.Ile306Ile	synonymous	Exon 9 of 17	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.918C>T	p.Ile306Ile	synonymous	Exon 9 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.918C>T	p.Ile306Ile	synonymous	Exon 9 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.915C>T	p.Ile305Ile	synonymous	Exon 9 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 3276 AN: 110911 Hom.: 97 Cov.: 22

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.000683

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.0243

GnomAD2 exomes AF: 0.0114 AC: 2088 AN: 183414 AF XY: 0.00940

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00861

GnomAD4 exome AF: 0.00639 AC: 7015 AN: 1097515 Hom.: 111 Cov.: 29 AF XY: 0.00645 AC XY: 2339 AN XY: 362897

African (AFR) AF: 0.0941 AC: 2482 AN: 26374

American (AMR) AF: 0.00676 AC: 238 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00201 AC: 39 AN: 19380

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30200

South Asian (SAS) AF: 0.0154 AC: 833 AN: 54130

European-Finnish (FIN) AF: 0.000865 AC: 35 AN: 40484

Middle Eastern (MID) AF: 0.0184 AC: 76 AN: 4135

European-Non Finnish (NFE) AF: 0.00339 AC: 2852 AN: 841536

Other (OTH) AF: 0.00996 AC: 459 AN: 46069

GnomAD4 genome AF: 0.0297 AC: 3301 AN: 110966 Hom.: 97 Cov.: 22 AF XY: 0.0250 AC XY: 831 AN XY: 33208

African (AFR) AF: 0.0930 AC: 2836 AN: 30486

American (AMR) AF: 0.0178 AC: 186 AN: 10439

Ashkenazi Jewish (ASJ) AF: 0.00227 AC: 6 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.0130 AC: 34 AN: 2623

European-Finnish (FIN) AF: 0.000683 AC: 4 AN: 5856

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.00370 AC: 196 AN: 52979

Other (OTH) AF: 0.0240 AC: 36 AN: 1498

Alfa AF: 0.0147 Hom.: 173

Bravo AF: 0.0346

EpiCase AF: 0.00551

EpiControl AF: 0.00427

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	-0.44
CADD	Benign	0.71
DANN	Benign	0.80
PhyloP100		-0.23
Mutation Taster		=99/1	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: rs12014115; hg19: chrX-129272617;