rs12007545

chrX-130137157-T-CchrX-130137157-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004208.4(AIFM1):c.996A>G(p.Gln332=) 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:7
• Conservation: PhyloP100: 0.203

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 -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 id is 136322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-130137157-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM1	NM_004208.4	c.996A>G	p.Gln332=	synonymous_variant	10/16	ENST00000287295.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM1	ENST00000287295.8	c.996A>G	p.Gln332=	synonymous_variant	10/16	1	NM_004208.4

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 3118 AN: 110679 Hom.: 100 Cov.: 22 AF XY: 0.0237 AC XY: 781 AN XY: 33013

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

GnomAD3 exomes AF: 0.00997 AC: 1827 AN: 183252 Hom.: 52 AF XY: 0.00811 AC XY: 549 AN XY: 67708

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 SAS exome AF: 0.0152

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

Gnomad4 AFR exome AF: 0.0941

Gnomad4 AMR exome AF: 0.00645

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000563

Gnomad4 OTH exome AF: 0.00840

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

Gnomad4 AFR AF: 0.0936

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.00152

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000870

Gnomad4 OTH AF: 0.0220

Alfa AF: 0.00452 Hom.: 129

Bravo AF: 0.0332

EpiCase AF: 0.00224

EpiControl AF: 0.00148

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

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 13, 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	-0.58
Cadd	Benign	0.59
Dann	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12007545; hg19: chrX-129271132;