rs12014115

chrX-130138642-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004208.4(AIFM1):c.918C>T(p.Ile306=) 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 (★★).

• 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:7
• Conservation: PhyloP100: -0.228

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 136320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-130138642-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM1	NM_004208.4	c.918C>T	p.Ile306=	synonymous_variant	9/16	ENST00000287295.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM1	ENST00000287295.8	c.918C>T	p.Ile306=	synonymous_variant	9/16	1	NM_004208.4

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 3276 AN: 110911 Hom.: 97 Cov.: 22 AF XY: 0.0244 AC XY: 808 AN XY: 33143

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

GnomAD3 exomes AF: 0.0114 AC: 2088 AN: 183414 Hom.: 53 AF XY: 0.00940 AC XY: 638 AN XY: 67850

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 SAS exome AF: 0.0155

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

Gnomad4 AFR exome AF: 0.0941

Gnomad4 AMR exome AF: 0.00676

Gnomad4 ASJ exome AF: 0.00201

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0154

Gnomad4 FIN exome AF: 0.000865

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00996

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

Gnomad4 AFR AF: 0.0930

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.00227

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.000683

Gnomad4 NFE AF: 0.00370

Gnomad4 OTH AF: 0.0240

Alfa AF: 0.0147 Hom.: 153

Bravo AF: 0.0346

EpiCase AF: 0.00551

EpiControl AF: 0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 11, 2016	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Severe X-linked mitochondrial encephalomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.71
Dann	Benign	0.80

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: rs12014115; hg19: chrX-129272617;